Exploring the multiple roles of guardian of the genome: P53
Egyptian Journal of Medical Human Genetics volume 21, Article number: 49 (2020)
Cells have evolved balanced mechanisms to protect themselves by initiating a specific response to a variety of stress. The TP53 gene, encoding P53 protein, is one of the many widely studied genes in human cells owing to its multifaceted functions and complex dynamics. The tumour-suppressing activity of P53 plays a principal role in the cellular response to stress. The majority of the human cancer cells exhibit the inactivation of the P53 pathway. In this review, we discuss the recent advancements in P53 research with particular focus on the role of P53 in DNA damage responses, apoptosis, autophagy, and cellular metabolism. We also discussed important P53-reactivation strategies that can play a crucial role in cancer therapy and the role of P53 in various diseases.
We used electronic databases like PubMed and Google Scholar for literature search. In response to a variety of cellular stress such as genotoxic stress, ischemic stress, oncogenic expression, P53 acts as a sensor, and suppresses tumour development by promoting cell death or permanent inhibition of cell proliferation. It controls several genes that play a role in the arrest of the cell cycle, cellular senescence, DNA repair system, and apoptosis. P53 plays a crucial role in supporting DNA repair by arresting the cell cycle to purchase time for the repair system to restore genome stability. Apoptosis is essential for maintaining tissue homeostasis and tumour suppression. P53 can induce apoptosis in a genetically unstable cell by interacting with many pro-apoptotic and anti-apoptotic factors.
Furthermore, P53 can activate autophagy, which also plays a role in tumour suppression. P53 also regulates many metabolic pathways of glucose, lipid, and amino acid metabolism. Thus under mild metabolic stress, P53 contributes to the cell’s ability to adapt to and survive the stress.
These multiple levels of regulation enable P53 to perform diversified roles in many cell responses. Understanding the complete function of P53 is still a work in progress because of the inherent complexity involved in between P53 and its target proteins. Further research is required to unravel the mystery of this Guardian of the genome “TP53”.
Despite 40 years of research studies about various functions of tumour suppressor protein P53, new roles of P53 are still a work in progress. “The TP53 gene (encodes for tumour protein 53), founded in 1979, has been extensively studied in cancer” . “The protein P53 is a transcription factor encoded by the gene TP53 which is the most commonly mutated tumour suppressor gene in human cancers, it performs multiple regulatory functions by receiving information, modulating and relaying the information, carrying out multiple downstream signals such as cellular senescence, cell metabolism, inflammation, autophagy, and other biological processes which control the survival and death of abnormal cells” [2, 3]. “P53 also plays a crucial role in determining cell’s response to various cellular stress like DNA damage, nutrient deficiency, and hypoxia by inducing gene transcription, which controls the process of cell cycle and programmed cell death (apoptosis)” .
Generally, in a cell, P53 is an unstable protein that is present in meagre amounts inside the cell because it is continuously degraded by Mouse double minute 2 homologue protein (MDM2) . These multiple functions of P53 attributed to its interaction with many target genes, which were discovered by gene ontology enrichment analysis . P53 has a complex array of functions, which makes it a challenging protein to study. This review explores multifaceted roles of P53, summarizes different mechanisms through which it inhibits cell proliferation, and explains its role in apoptosis, autophagy, and metabolism.
Outline of the P53 family
TP53 belongs to a large family of genes whose other members include TP63 and TP73, which have broad and complementary roles. “As species evolved, TP53 of higher eukaryotic species got deviated from its family members TP63 and TP73 before the advent of large aquatic animals” . “TP53 has evolved to exhibit tumour-suppressive activities, a unique characteristic not shown by its homologs TP63 and TP73 that exhibits a role in embryogenesis” . “P53 family members have a preserved framework, as shown in Fig. 1. In the figure there is an N-terminal transactivation (TA) domain”  which is a 42 amino acid sequence and it is vital for transcriptional activity, “replacing the amino acids Phenylalanine 19, Leucine 22 or Tryptophan 23 results in transactivation deficient mutant proteins” [11, 12], a proline-rich (PR) region that contributes to transcription activation, is essential for restricting cell growth  and is a highly conserved sequence-specific DNA-binding domain (DBD) that is present in between amino acids 100, and 300 forms a protease-resistant core [14, 15] that “identifies a core sequence pattern of 10-base pairs (PuPuPuCA/T.A./TPyPyPy, where Pu=purine, Py=pyrimidine)” .
“The DNA binding domain (DBD) tucked into a four- and five-stranded β sheet scaffold, which is anti-parallel and two-α helices that interact with DNA” . “Most of the cancer-associated mutations are present in this region . Oligomerization domain (OD) consists of amino acids 324 to 355 and mediates in the formation of P53 tetramer, which is a dimer of dimers” . P53 cannot form tetramers when this region substitutes hydrophobic amino acids . This domain also contains a nuclear export signal (NES), which is masked by P53 tetramerization resulting in trapping of P53 inside the nucleus, whereas monomers and dimers are transported to the cytoplasm . “One study suggested that oligomerization is crucial to cell fate decisions” . “Studies have shown that alternative splicing at C-terminal exons of both TP63 and TP73 yields three isoforms of TP63 (α, β, γ) and seven isoforms of TP73 (α, β, γ, δ, ε, ζ, η) furthermore alternative promoter region in the gene family show possible transcriptional start sites that give rise to N-terminal truncated isoforms like ∆40P53, ∆133P53, ∆Np63, ∆Np73, these isoforms can show dominant-negative effects on P53, P63 and P73, on top of that N-terminal truncated isoform of P53 (∆133P53) formed from the internal promoter in intron 4 of TP53 gene lack transactivation and proline-rich domains” .
P53 and DNA damage response
P53 plays a central role in DNA damage response and considered “Guardian of the Genome”. DNA damage response is dependent on the nature of the stress signal, the cell type, timing, and intensity of the stress signal. “DNA damage promotes Post-translational modifications (PTMs) on P53” , “whereas oncogenic stress activates Alternative reading frame (ARF) tumour suppressor protein to inhibit MDM2” . “In response, P53 can activate cell cycle arrest, repair the damaged DNA, activates specific cell death pathways, and metabolic changes in the cell, as shown in Fig. 2” . “DNA damage causes P53activation which induces an array of genes spanning multiple functions, using various genetic studies the best known P53 targets”  are (i) DNA damage response genes (e.g., damage specific DNA-binding protein 2 (DDB2) and XPC complex subunit, DNA damage recognition, and repair factor (XPC), (ii) “cell cycle arrest genes (cyclin-dependent kinase inhibitor1 (CDKN1A) encoding protein P21, Growth arrest and DNA-damage inducible alpha (GADD45A)” , (iii) “genes involved in apoptosis (BCL2 binding component 3 (BBC3) (also known as PUMA) and BCL-2-associated X, Apoptosis regulator (BAX)” , (iv) metabolism (TP53-induced glycolysis regulatory phosphatase (TIGAR) and Aldehyde dehydrogenase one family, member A3 (ALDH1A3), and (v) “Post-translational regulators of P53 (MDM2 proto-oncogene and PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) (also known as Wild-type P53-induced phosphatase 1(WIP1)” . Expression profiling study identified many target genes of P53 whose number ranged from less than 100 to more than 1500 based on the conditions of P53activation and approaches used for data processing , “the main drawback was that they could not differentiate among the direct and indirect targets of P53” .
P53 dynamics in DNA damage response
P53 dynamics are also important in DNA damage response, and many profiles of P53 relating to time were identified using various models. “One important study conducted by Purvis et al. by using a mathematical model to explain the feedback loop of various stress signals like inactive P53, active P53, MDM2, and WIP1, based on the assumption that a constant source produced inactive P53 which was degraded by MDM2 and whenever the cell subjected to DNA damage, would result in the conversion of inactive P53 to active P53, and this conversion rate was reliant on the degree of DNA damage” . “Later on, the active form of P53 is degraded by MDM2 protein” . “In the model, Purvis showed that the levels of MDM2 levels were increased by P53 stimulation, whereas DNA stress induces reduced levels of MDM2 protein” .
“This model showed that various P53 targets associated with different cell fates like cell cycle control and DNA repair (CDKN1A), growth arrest and DNA-damage-inducible protein alpha (GADD45A), MDM2 and post-translational regulators of P53 (protein phosphatase 1 (PP1)) displayed a periodic fluctuation similar to P53 protein, for example when P53 was at the sustained level some target proteins like P21 and MDM2 also increased to a sustained level” . “A significant observation in this study was that P53 target genes for apoptosis and senescence such as Apoptotic peptidase activating factor 1 (APAF1), BAX, PML nuclear body scaffold (PML) and Yippee-like 3 (YPEL3) were induced only at sustained P53 level but not by P53 pulse” . “This model also studied how P53 dynamics influenced the cell fate and showed that cells with pulsing P53 dynamics recovered well from DNA damage whereas sustained P53 levels in cells lead to cellular senescence” . More of such studies are necessary for understanding the effect of P53 dynamics on cell fate decisions.
P53 induces cell cycle arrest
In response to various cellular stress, P53 can activate the transcriptional upregulation of CDKN1A, which encodes for cell cycle inhibitor P21 . P53 can also activate other genes like GADD45A, which also contributes to cell cycle arrest . Following DNA damage, a myriad of DNA-protein activation occurs. For example, DNA damage kinases like ATM serine/threonine kinase (ATM) or ATR serine/threonine kinase (ATR) are activated and phosphorylate various proteins Checkpoint kinase 1 (CHEK1) or Checkpoint kinase 2 (CHEK2), Nibrin (NBN of the MRN repair complex), MDM2, and P53 to arrest cell cycle . “In a cell cycle to progress from G1 to S phase, it requires active G1 cyclin/CDK complexes (Cyclin-dependent kinase), activated P21 inhibits cyclin D/CDK4 and cyclin E/CDK2 complex and thus blocks the phosphorylation of protein substrates essential for the onset of S phase” . “Cyclin/CDK complexes also phosphorylates tumour suppressor RB transcriptional corepressor 1 (RB1), which results in dissociation from E2F family transcriptional factors and progression of DNA synthesis” . “P21induced by P53 also inhibits phosphorylation of RB protein and blocks cell cycle, thus linking two tumour suppressor genes in same cell cycle checkpoint” .
“Numerous studies showed evidence for the above mechanism, for example, cells when exposed to gamma radiation lead to the expression of P21 causing inhibition of CDK activity” . “In another study defect in DNA damage-induced G1/S checkpoint was seen in mouse embryo fibroblast derived from a cyclin-dependent kinase inhibitor 1(P21WAF1/CIP1) deficient mice” . “The cell cycle arrest activity of P21 is well studied, but there are many other P53-induced genes that play a role in cell cycle arrest” . “For example, protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) is a growth-suppressive protein phosphatase, which is a vital regulator of DNA damage response and oncogenesis may also play a role in G1/S phase arrest” . “WIP1 dephosphorylates the DNA damage-induced phospho sites in H2AX variant histone (H2AX), ATM and CHK2 kinases” [38, 39], “leading to reduced signalling and activation of P53 which is a transcription factor for turning ‘ON’ expression of many genes involved in DNA repair, cell cycle, cell death” [40, 41]. Transcription factor P53 also targets Cyclin G1, which is a novel member of the cyclin family. P53-mediated transcriptional upregulation of 14-3-3 phospho-serine/phospho-threonine binding proteins (14-3-3σ) expression also plays a role in cell cycle arrest. Upon DNA damage, dephosphorylated P53 binds to promoter region 1.8 kb upstream of 14-3-3σ transcription start site leading to increased expression of 14-3-3σ which results in detachment of CDK1/Cyclin B complex in the cytoplasm and blocked interaction of Cell division control protein 2 homologue (CDC2) with CDK1 and entry of cell into mitosis thus sparing time for repair of DNA [42,43,44]. .
P53 role in cellular senescence
“Temporary cell cycle arrest may not be the permanent solution because a cell with oncogenicity that cannot repair may resume proliferation and develop a tumour” . “Cellular senescence is permanent cell cycle arrest that inhibits further replication of the cell but leaves a functioning cell” . “P53-induced cellular senescence occurs in cells in which telomeres shortening is seen as well as in cells with oncogene activation and oxidative damage” . Cellular senescence mediates via P53-induced transcriptional activation of the cyclin-dependent kinase (CDK) inhibitors P21CIP1 (CDKN1A) and P16 INK4A (CDKN2A) , but it is not enough on its own . The dynamics of stress can influence senescence, that is, if the stress that initiates senescence is transient, then P53 induction can implement a quiescent state and activate the DNA repair process and, after the stress resolves, the cell can start cycling . Persistent stress or prolonged P21-mediated cell cycle arrest can activate P16INK4A, an inhibitor of CDK4 and CDK6, as well as subsequent activation of the RB1 transcriptional regulator, resulting in long-lasting cell cycle arrest . The role of P21CIP1 may be to initiate senescence, whereas P16INK4A may be responsible for durable growth arrest .
“Senescence is also associated with β-galactosidase (SA-β-gal) activity and expansion of cytokines that constitute the senescence-associated secretory phenotype” . Apart from P21INK4A, there are other target genes like PML nuclear body scaffold (PML) and SERPINE1 (Serpin family E member 1) also known as “Plasminogen activator inhibitor-1” (PAI-1) which are transcriptionally activated by P53 and plays a role in senescence . “Kortlever and his colleagues reported that PAI-1 is not only an essential marker but also a crucial advocate of cellular senescence in vitro” . “They examined the role of P53 and its target gene PAI-1 in cellular senescence and stated that fibroblasts with negative P53-and PAI-1-were immune to cellular senescence and multiplied longer than wild-type fibroblast” . “There most prominent observation was that in the absence of cellular P53, overexpression of PAI-1 is sufficient to induce senescence in fibroblasts and they reported that PAI-1 regulates cellular senescence through PI3K-PKB-GSK3-cyclin D1 pathway” .
Another important P53-induced target gene is PML nuclear body scaffold (PML); it is a ubiquitously expressed nuclear phosphoprotein that belongs to the tripartite motif-containing (TRIM) protein superfamily . The mechanism through which PML plays a role in senescence involves the RB and P53 tumour suppressor proteins [52, 53], which can directly interact with PML . “Induction of cellular senescence not only results in irreversible cell cycle arrest but also releases Senescence-associated secretory phenotype (SASP)” . A senescent cell is a persisting metabolically active cell that has undergone an array of changes in protein secretion and expression, finally developing SASP, which is phenotype and named as senescence-messaging secretome . “SASP also play a role in tumorigenicity based on P53 status, for example in the stellate cells of liver stroma, the senescent stellate cells secrete factors that induce tumour clearance activity in nearby macrophages which are mediated by P53, whereas P53 null stellate cells employee macrophages that activate tumorigenesis” . “In the colon, P53 deletion results in changes like SASP, increasing the expression of Tumour necrosis factor-alpha (TNF-α) and thus increasing its ability to induce invasion and multiplication of tumour cells” .
P53 role in the DNA repair process
“Under the low level of cellular stress and when there is a scope for the repair process, P53 activates a temporary cell cycle arrest and initiates the DNA repair process, thus limiting the proliferation of oncogenic mutated cells” . The important P53-induced transcriptional gene target in this process is CDKN1A, which encodes the protein P21, which causes a transient arrest of cell cycle along with its role in cellular senescence [30, 36]. In the phase, when the cell cycle arrests, P53 is involved in the regulation of DNA repair pathways . These repair pathways are specific for a particular class of DNA lesions and directed at re-establishing the integrity of the molecular structure of DNA . The DNA repair system is a very complex network, and it is one of the most critical and powerful determinants of cell fate for survival, senescence, or apoptosis .
The repair mechanisms for Single-strand breaks (SSBs) and Double-stranded breaks (DSBs) are outlined as, “In eukaryotes, in response to SSBs and DSBs there are five main DNA –repair processes, Nucleotide-excision repair (NER), Base-excision repair (BER) are involved in the repair of DNA lesions affecting only one strand of the double helix (SSB), Non-homologous end-joining (NHEJ) and Homologous recombination repair (HRR) are involved in the repair of DNA lesions affecting both strands of the double helix (DSB), the Mismatch repair process is involved in the repair of mismatched nucleotides, insertion and deletion loops due to replication errors” [62,63,64]. Single-strand annealing (SSA) is one more unique DNA repair process that makes use of components from both HRR and NHEJ . P53-mediated response to DNA damage may not be a part of its function as a tumour suppressor . However, it does support cell activity. P53 target genes in the NER process are DDB2 and XPC, which encodes for the proteins damage-specific DNA-binding protein 2 and XPC complex subunit, DNA damage recognition, and repair factor [67, 68].
“On prolonged exposure to U.V. radiation through sunlight leads to the formation of DNA lesions like Cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts (6-4PPs) which can lead to the development of genome instability and skin cancers if not repaired” [69, 70]. “Removal of this mutagenic DNA lesion takes place by the NER pathway, and it is activated by two different DNA damage identification paths, which depend on the precise location of the DNA lesion. Furthermore, NER reaction is transcription induced and induced by RNA polymerase II (POLII) - blocking lesions and thus eliminates DNA lesion from that strand of DNA in which genes are under transcription” [71, 72]. Conversely, Global-genome NER (GG-NER) utilizes lesions sensors DDB2 and XPC to identify and eliminate DNA lesions from transcribed as well as non-transcribed templates of the whole genome [73, 74].
“P53 induced Ribonucleotide Reductase Regulatory TP53 Inducible Subunit M2B (RRM2B) gene encodes for Ribonucleotide Reductase (RR) which helps in DNA repair process by providing precursors” . Proliferating cell nuclear antigen (PCNA) is a ubiquitous nuclear protein, which is a crucial part of replication fork also plays a vital role in the DNA repair process by providing replicative DNA polymerases and other proteins required for duplication of entire genome [76,77,78]. P53 can also activate DNA Polymerase Eta (POLH) and specifically recruit a DNA polymerase to replicate damaged DNA  accurately. In humans, the POLH gene encodes for DNA polymerase eta (Pol η); the other name for POLH gene is Xeroderma pigmentosum variant (XPV) gene because of a mutation in a group of patients, diagnosed with XP disease that did not carry mutations in NER gene . Cells have many repair mechanisms through which they can repair there DNA damage lesions . However, for those cells which have unrepaired lesions, the replication process of damaged DNA utilizes translesion synthesis (TLS) polymerases, and these polymerases can bypass the lesions . “Human cells can develop genetic syndromes like Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) as a result of the failure of these mechanisms furthermore XP and CS exhibit complex phenotypes of cancer or severe neurodegeneration and ageing” [81, 82].
Role of P53 in apoptosis
Apoptosis is a significant type of regulated cell death in human cells, and it is an evolutionarily conserved process with many ranges of functions like maintenance of tissue homeostasis [83, 84], prevention of cancer , and essential for proper embryonic development . “Apoptosis winds up in the activation of Cysteine-aspartic proteases (CASPASES), which causes proteolytic degradation of intracellular components followed by phagocytic clearance with least stress to the surrounding environment of cells and tissues” [87, 88].
The activation of caspases ensues by one of the two pathways—the extrinsic pathway and the intrinsic pathway. “The extrinsic apoptotic pathway also called as death receptor-mediated is initiated by binding of various death ligands such as FS-7-associated surface antigen (FAS) or TNF superfamily member 10 (TNFSF10, also known as TNF-related apoptosis-inducing ligand (TRAIL) to Death receptors (DR) family member like Tumour necrosis factor (TNF) –receptor superfamily member 10a (TNFRSF10A, also known as TRAILR1), Tumour necrosis factor (TNF) – receptor superfamily member 10b (TNFRSF10B, also known as TRAILR2), Fas cell surface death receptor (FAS, also known as CD95) or TNF receptor superfamily member 1A(TNFRSF1A) present at the cellular membrane and thus leads to activation of caspases (mainly caspases 8) resulting in extensive cleavage of caspases substrates and cell death” . “The intrinsic apoptotic pathway also named as the mitochondrial pathway initiated by a wide variety of intracellular stresses such as cytokine distress, DNA damage and endoplasmic reticulum dysfunction which activates single significant event that is Mitochondrial outer membrane permeabilization (MOMP) leads to the release of cytochrome c from the inner mitochondrial membrane into the cytoplasm through a cytoplasmic complex (apoptosome) which activates the cascade of caspases leading to cell death” .
“One of the major biological roles of wild-type P53 is its capability to induce apoptosis in genetically unstable cell” . “P53 transcriptionally activates many pro-apoptotic BCL-2 family proteins like BCL2 antagonist/killer 1 (BAK1), BCL-2-associated X, Apoptosis regulator (BAX), PMAIP1 (Phorbol-12-myristate-13-acetate-induced protein 1 also known as NOXA) and P53 upregulated modulator of apoptosis PUMA (also known as BBC3 (BCL-2-binding component 3)) which are essential elements of MOMP in reply to death signal” [92, 93]. “P53 can directly interact with pro-apoptotic and anti-apoptotic proteins present in the cytoplasm and the membrane of mitochondria” ; thus, “P53 can act as both a sensitizer as well as an activator of apoptosis” . “However, P53 can also inhibit B-cell Lymphoma 2 (BCL-2) and BCL2 like 1 (BCL2L1) which enable pro-apoptotic members (BAK or BAX) to detach from heterodimer complexes following the oligomerization of BAX and BAK into mitochondrial outer membrane (MOM) thus forming lipid openings into MOM through which the initiators of apoptosis released in response to death signal” [95,96,97,98,99].
“P53 can activate Apoptotic peptidase activating factor 1 (APAF1) and cytochrome c, which releases from mitochondria binds to APAF1 and procaspase 9 to form apoptosome” [100, 101]. Another P53 target gene Apoptosis-enhancing nuclease (AEN) also supports apoptosis by digesting double-stranded DNA . P53 also upregulates the ceramide synthase-encoding genes like Ceramide Synthase 5 (CERS5) and Ceramide Synthase 6 (CERS6)  and induces ceramide production  which can activate apoptosis. “Even though most of the P53 target genes encode for apoptosis-inducing proteins, the P53 target, TP53 Regulated Inhibitor of Apoptosis1 (TRIAP1), encodes for an inhibitor of apoptosis” . The decision between apoptosis and cell survival depends on the members of the BCL-2 family, regulated by P53 in both transcription-dependent and independent manner.
Role of P53 in autophagy
“Another cellular pathway triggered by cellular stress and P53 is autophagy” . This mechanism can restrain the activity of P53 by preventing various signals for cellular stress like DNA damage and oxidative stress and by also directly degrading P53 . “On the other hand, P53 can activate various target genes that play a role in autophagy like DNA-damage-regulated autophagy modulator 1 ((DRAM1), UNC-51-like autophagy-activating kinase 1 (ULK1) and cathepsin D” [108,109,110]. “P53 mediated autophagy also plays a role in suppression of tumour” . The following are the target genes for P53: Tuberous Sclerosis Complex subunit 2 (TSC2), Phosphatase and Tensin Homologue (PTEN), protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), or Sestrins 1 and 2 which are PRKAA2 activators, and these pro-autophagic factors further signal the autophagic process through mechanistic target of rapamycin kinase (mTOR) inhibition [112,113,114,115]. “Damage regulated autophagy modulator 1 ((DRAM1) is also a target gene for P53 in cell stress response , and (DRAM1) also denotes a lysosomal protein that intervenes in various stages of autophagosome formation” .
“Several pro-apoptotic proteins transactivated by P53 also play a role in the activation of autophagy” [117, 118]. “This can occur in two ways, either by downregulating the expression of genes like BCL-2, BCL2L1 and BCL2 Interacting Protein 3 (BNIP3), or by upregulating the expression of BAX, BAD or BBC3 which ultimately releases Beclin-1 that initiates autophagy” . P14ARF (encoded by CDKN2A) is a tumour suppressor protein that is regulated by P53, and it can also induce autophagy by directly interacting with BCL2L1 [120, 121]. Death-associated protein kinase 1 (DAPK-1) is an essential regulator of both apoptosis and autophagy in the ER stress-induced apoptotic pathway . It can activate autophagy either by phosphorylating Beclin-1, which inhibits DAPK-1 degradation by anti-apoptotic proteins or possibly by inhibiting the anti-autophagic Microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A)-interacting Microtubule-associated protein 1B (MAP1B) [123, 124]. The effect of P53 on autophagy may be dependent on its intracellular localization. Under cellular stress, P53 activates autophagy by translocating to the nucleus, whereas, under normal physiological state, cytoplasmic P53 inhibits autophagy. “This inhibition of autophagy by cytoplasmic P53 is via the same canonical PRKAA2-mTOR pathway and independent of P53 transcriptional activity” . “Contrary to nuclear P53, cytoplasmic P53 protein inhibits the AMP-dependent kinase (a positive regulator of autophagy) and activates mTOR” . A vital observation is that when P53-deficient cancer cells are exposed to hypoxia and nutrient depletion, the survival of these cancer cells improved because of enhanced autophagy. “This study also highlighted that inhibition of P53 degradation barred the activation of autophagy in several cell lines” .
Role of P53 in metabolism
“P53 is also involved in the metabolism by helping the cells to adapt and survive under nutrient-deprived conditions like glucose , glutamine  and serine deprivation” . “In response to nutrient deprivation the temporary activation of P21 (CDKN1A) plays a role in protective responses by arresting cell cycle –for example in response to serine starvation, P21 helps in de novo synthesis of serine into glutathione rather than nucleotide synthesis”  and also “in response to cysteine starvation P21 helps in delaying ferroptosis” . Thus, P53 plays an essential role in nutrient deprivation by initiating alternative pathways to maintain cell survival and also plays a role in the death of the cells when recovery seems impossible.
P53 plays an essential metabolic role by decreasing the rate of glycolysis and supplementing mitochondrial respiration. It downregulates the initial step of glycolysis (cells take up the glucose) by directly repressing the expression of various glucose transporters like Solute carrier family 2 member 1 (SLC2A1, also known as Glucose transporter type 1 (GLUT1)) and Solute carrier family 2 member 4 (SLC2A4, also known as Glucose transporter type 4 (GLUT4))  and indirectly P53 controls Solute carrier family 2 member 3 (SLC2A3, also known as Glucose transporter type 3 (GLUT3)) expression by repressing IKK-NF-κB pathway . “P53 can also inhibit glycolysis by activating TP53-induced glycolysis regulatory phosphatase (TIGAR), also known as fructose-2,6-bisphosphatase and this activation allows TIGAR to hydrolyze fructose-2,6-bisphosphate which is an allosteric activator of Phosphofructokinase 1 (PFK1, the enzyme for the rate-limiting step in glycolysis) which results in low levels of fructose-2,6-bisphosphate” .
“P53 inhibits glycolysis by downregulating the expression of glycolytic enzyme Phosphoglycerate mutase (PGM), which act as a catalyst for the conversion of 3-phosphoglycerate into 2-phosphoglycerate during glycolysis in fibroblasts in a P53-mediated transcription-independent manner”  but “P53 can directly transactivate the transcription of PGM in cardiac myocytes”. “Another mechanism by which P53 inhibits the transport of glucose is by direct transcription of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD), which results in inhibition of translocation of GLUT1 at the cellular membrane” . “P53 can also inhibit the expression of mitochondrial Pyruvate dehydrogenase kinase 2 (PDK2) which is a negative regulator of Pyruvate dehydrogenase (PDH)” —resulting in increased activity of PDH and this increased activity stimulates the conversion of pyruvate to acetyl-CoA for use in the TCA cycle and enhances mitochondrial respiration. Another gene that is activated by P53 is Parkin RBR E3 ubiquitin-protein ligase (PRKN), which encodes for an E3 ubiquitin ligase called as parkin  that increases the expression of Pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which is a part of PDH complex.
“P53 transcriptional target gene Glutaminase 2(GLS2) is a mitochondrial protein that catalyzes the hydrolysis of glutamine to produce glutamate, which is promoted into mitochondrial TCA thus supporting mitochondrial respiration and production of ATP” [135, 136]. P53 also controls lactate levels in cancer cells by suppressing the lactate transporter Malonyl-CoA-acyl carrier protein transacylase (MCAT), which results in lactate accumulation that inhibits glycolytic rate in cancer cells . “P53 also regulates the expression of Synthesis of cytochrome c oxidase 2 (SCO2), required for mitochondrial cytochrome c oxidase assembly, thus regulating the normal functioning of Electron transport chain (ETC) and oxidative phosphorylation” . P53 directly induces the expression of mitochondrial Apoptosis-inducing factor mitochondria associated 1 (AIFM1), which plays a role in maintaining ETC . In another study, P53 also induces Mitochondria-eating protein (MIEAP), which promotes the removal of oxidized proteins and sometimes mitochondria itself to aid mitochondria . Thus, “On the whole, P53 seems to enhance energy metabolism through mitochondrial respiration and maintain mitochondrial integrity over glycolysis thus opposing the Warburg effect (which increases aerobic glycolysis seen in rapidly dividing normal and cancer cells), but some studies challenge these ideas for example, “In telomerase knockout mice with severe telomere dysfunction activation of P53 triggers the suppression of PGC-1α and PGC-1β (positive regulators of mitochondrial synthesis) which leads to mitochondrial dysfunction and reduced oxidative phosphorylation” . Thus, it implies that the effect of P53 on glucose metabolism depends on cellular context.
“P53 is also involved in Pentose phosphate pathway (PPP), an alternative pathway of glycolysis to supply ribose required for the synthesis of nucleotides and NADPH for reductive biosynthesis and antioxidant control by regulating TIGAR which promotes metabolic intermediates of glycolysis like fructose-6-phosphate to move towards oxidative PPP or through activation of AKT serine/threonine kinase 1 (AKT1) which increases PPP gene expression” [142, 143]. P53 can also inhibit PPP through direct binding and inhibition of Glucose-6-phosphate dehydrogenase (G6PD), which is an essential enzyme of PPP . P53 also regulates gluconeogenesis. However, the role is not clear since it reported that P53 could promote  as well as inhibit  the expression of enzymes involved in gluconeogenesis. “P53 promotes gluconeogenesis through direct activation of Pantothenate kinase-1 (PANK1), which catalyzes the initial and rate-limiting step in CoA synthesis” . “In one study, it was reported that stabilization of P53 in response to starvation is crucial for gluconeogenesis and catabolism of amino acid in the liver” . “Goldstein et al. reported that P53 activation leads to induction of enzymes involved in gluconeogenesis like Glucose-6-phosphatase catalytic subunit (G6PC), Phosphoenolpyruvate carboxykinase-1(PCK1) and by providing glycerol through P53-dependent activation of Glycerol kinase (GK) or glycerol transporters like aquaporin 3 and aquaporin 9” . “Conversely, P53 can suppress gluconeogenesis by activation of deacetylase Sirtuin 6 (SIRT6), which deactivates Forkhead box protein O1 (FOXO1), a positive regulator of Phosphoenolpyruvate carboxykinase-1 (PCK1) and Glucose-6-phosphatase catalytic subunit (G6PC)” .
Apart from regulating glucose metabolism, P53 also plays a role in regulating lipid metabolism by enhancing Fatty acid oxidation (FAO) and inhibiting fatty acid synthesis. Thus it is believed that P53 acts as a negative regulator of lipogenesis . P53 regulate several genes that directly plays a role in lipid metabolism including three carnitine acyltransferases Carnitine O-Octanoyltransferase (CROT), Carnitine palmitoyltransferase 1A (CPTA1), and Carnitine palmitoyltransferase 1C (CPT1C) [151, 152]. “P53 induced activation of Carnitine palmitoyltransferase1C (CPT1C) promotes the transport of activated fatty acids into the mitochondria” . “Lipin1 (LPIN1) is another gene that is activated by P53 and in response to nutrient deprivation” . “LPIN1 translocates to the nucleus where it acts as a transcriptional coactivator and activates the expression of genes involved in FAO, resulting in increased FAO” . P53 inhibits fatty acid synthesis (FAS) through direct protein-protein interaction, for example, P53 binds directly to and inhibits G6PD, which results in reduced NADPH production and thus decreased FAS .
“P53 downregulates the expression of Sterol regulatory element-binding proteins (SREBP), which plays a key role in driving expression of FAS genes” . P53 mutant protein binds directly to SREBP and increases their transcriptional functions, which result in increased activity and thus increased sterol biosynthesis in human tumour’s [156, 157]. In response to metabolic stress, P53 is activated by AMPK via serine 15 phosphorylation, which results in temporary cell cycle arrest . In contrast, under genomic stress P53 can activate AMPK via sestrin 1 and sestrin 2, leading to inhibition of mTOR and thus arrest of cell growth and proliferation . Conversely, mutant P53 binds to and inhibits PRKAA2 resulting in increased FAS and invasive cell growth of tumour cells . “P53 is involved in transcriptional inhibition of Stearoyl-CoA-desaturase 1 (SCD1), which is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the synthesis of Mono-unsaturated fatty acids (MUFAs)” .
Amino acid metabolism
P53 also regulates amino acid metabolism via transcriptional regulation of GLS2. “In response to impaired pyruvate oxidation P53 regulates GLS2, which replenishes TCA intermediates and also contributes to various metabolic pathways, this response is essential to continue the redox status of cells by driving glutathione production” [135, 136, 158]. “In response to glutamine deficiency, firstly P53 induces the expression of arginine transporter Solute carrier family 7 member 3 (SLC7A3) which increases transient levels of arginine inside the cell to endure mTORC1 activity” , “secondly P53 induces the expression of amino acid aspartate transporter SLC1A3 to support cellular respiration and synthesis of nucleotides” . “Serine deprivation may initially promote survival of the cell via MDM2/ATF-4 facilitated control of serine synthesis and also through the P53-P21 pathway, but when this deprivation is prolonged or severe, it may start a brutal cycle during which P53 induced suppression of Phosphoglycerate dehydrogenase (PHGDH) and activation of PMAIP1 and PUMA via Activating transcription factor 4(ATF4) results in cell death” [161, 162]. Overall, many of the P53 related metabolic functions rest on the capability of the cells to handle metabolic stress and survive the stress.
“The cancer genome sequencing showed that 42% of cases across 12 types of tumour bear TP53 mutant” , but it is to be noted that the TP53 mutation rate also varies across tumour types. “Most TP53 mutations in cancer are missense mutations contributing to nearly 75% and located in the DNA-binding core domain that results in disrupting DNA binding and oncogenic gain-of-function leading to exacerbation of tumour progression” . Various mouse models have shown that restoration of wild-type P53 function in cancer cells results in the induction of tumour cell death and tumour eradication. Thus, P53 reactivation can be a crucial strategy to fight cancer, and various small molecules identified to rescue and reactivate missense-mutant P53 protein as well as by induction of mutant P53 degradation (Fig. 3). These small molecules bind and stabilize mutant P53, but the accurate and precise mechanism of the refolding of mutant-P53 is not entirely clear. Another mechanism of P53 reactivation is through inhibition of MDM2-P53 interaction. Various compounds have been identified that reactivate P53 by blocking MDM2-P53 interaction.
Compounds that restores wild-type P53 activity
In Table 1, we have provided an overview of small molecules that directly target mutant P53 via reactivation of its tumour-suppressive transcriptional activity.
Compounds that deplete mutant P53
Another method to target oncogenic mutant P53 is via compounds that particularly deplete mutant P53 with minimal effect on wild-type P53. “The underlying principle of depleting mutant P53 based on the observation that mutant P53 proteins are inherently unstable in healthy cells, and it can accelerate tumour development once it is stabilized” .
In Table 2, we have provided an overview of small molecules that directly target and degrade mutant P53.
“In human cancer cells, mutant P53 shows more stability than wild-type P53, mainly because of the interaction of mutant P53 with the HDAC6/HSP90 chaperone complex” . “Treatment of cancer cells with 17-AAG (first HSP90 inhibitor), an analogue of Geldanamycin promotes degradation of various P53 mutants by inactivating HSP90 and decreases the viability of cells carrying mutant P53” . “Ganetespib, also known as STA-9090, was shown to display > 50-fold more potency than 17-AAG in degrading P53R175H and P53R248Q using mouse models” . Currently, there are more than a dozen of HSP90 inhibitors under preclinical and clinical studies.
Histone deacetylase inhibitors
“HDAC inhibitors can reduce the enhancement of mutant P53. Blagosklonny et al. reported the first line of evidence of histone deacetylase inhibitors (HDACi) such as trichostatin A and FR901228, on mutant P53 (P53R175H, P53R280K, P53V274F, and P53P223L)” . “Suberoylanilide hydroxamic acid (SAHA, also known as Vorniostat) is an HDACi that inhibits class I, II, and IV HDACs resulting in disruption of HDAC6/HSP90, mutant P53 complex. This disruption leads to mutant P53 ubiquitination by MDM2 and CHIP” [195, 207]. “SAHA shows higher cytotoxic effects on cancer cells carrying mutant P53 than wild-type or null for P53” . “SAHA also increases the sensitivity of cancer cells to camptothecin, a topoisomerase inhibitor in a mutant P53-dependent manner” . “Interestingly, HSP90 inhibitors synergize the effect of SAHA on the degradation of mutant P53 and inhibition of tumour cell growth both in vitro and in vitro” . “Romidepsin (Istodax®) is another selective inhibitor of HDACs, was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the U.S. FDA” . “It is a natural product discovered from the cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample” .
“Spautin-1 is a derivative of MBCQ (4-((3, 4-methylenedioxybenzyl) amino)-6-chloroquinazoline), which identifies as a small molecule designed for inhibition of macroautophagy” . “Spautin-1inhibits ubiquitin-specific peptidase 10 (USP10) and USP13, and promotes degradation of Vps34-PI3 kinase complexes (Phosphatidylinositol 3-kinase) (a key regulator of autophagy) resulting in inhibition of autophagy” . “Spautin-1 also inhibits EGFR (Epidermal growth factor receptor) phosphorylation and the activation of its downstream signalling leading to cell cycle arrest and apoptosis of PCa (Prostate cancer) in a USP10/USP13 independent manner” .
“MCB-613 causes rapid ubiquitination, nuclear export, and degradation of mutant P53R175H via a lysosome-mediated pathway, resulting in cancer cell death” . “Steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) are emerging as targets in cancer therapy. MCB-613 acts as a potent SRC small molecule stimulator (SMS) and super-stimulate SRC’s transcriptional activity” . “MCB-613 increases SRC’s interactions with various other coactivators and significantly induces E.R. (endoplasmic reticulum) stress that results in the generation of ROS and ultimately kills cancer cells” .
“Various mechanistic studies showed that lovastatin treatment inhibits the mevalonate-5-phosphate pathway and consequently induces CHIP (carboxyl terminus of Hsp70-interacting protein) ubiquitin ligase-mediated nuclear export, ubiquitylation, and mutant P53 degradation by inhibiting the interaction of mutant P53 with DNAJA1 (DnaJ Heat Shock Protein Family (Hsp40) member A1)” . “Treatment with lovastatin diminishes in vitro and in vitro tumour growth only in P53 mutant cancer cells, but not in P53-wildtype cancer cells” . “Thus, statins induced inhibition of the mevalonate pathway may signify a new and practical approach to kill P53 mutant cancer cells” .
“Gambogic acid (GA) is a xanthone extracted from the resin of Garcinia hanburyi tree. GA induces nuclear exports of mutant P53 for ubiquitination and subsequent degradation mediated by CHIP ubiquitin ligase” . “GA prevents the mutant P53-Hsp90 complex formation but enhances the mutant P53-Hsp70 complex formation” . “Furthermore, gambogic acid induces the degradation of cancer cells carrying mutant P53R280K and P53S241F proteins via autophagy” . “Gambogic acid inhibits the invasion and migration of transforming growth factor β1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) of the orthotopic model of A549 cells in vitro” . Gambogic acid also suppressed the EMT induced by TGFβ1 and tumour necrosis factor α by inhibiting the nuclear factor-kappa B (NF-κB) pathway . “In the xenograft pancreatic cancer model, the combination of gambogic acid and gemcitabine significantly repressed tumour growth, and Immunohistochemistry results demonstrated the downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment” .
Reactivation of P53 by MDM2 inhibitors
“MDM2 is the negative regulator of the TP53 gene and forms an autoregulatory feedback loop that controls the cellular levels of P53 and MDM2, as given in Fig. 4” . Ubiquitination and degradation of P53 is induced by MDM2, which acts as a unique E3 ubiquitin ligase protein. Small molecules that block the MDM2-P53 interaction and reactivate the P53 function seem to be a promising strategy for cancer treatment retaining wild-type P53. Many of these small molecules have also entered clinical trials.
In Table 3, we have provided an overview of small molecules that block MDM2-P53 interaction and reactivate the TP53 gene.
Role of P53 in diseases
P53 influences the onset of various lifestyle-related diseases like type 2 diabetes and obesity by altering the regulation of metabolism at the individual level . “Minamino and his colleagues first reported the evidence of linking P53 to the development of type 2 diabetes. They reported that diet-induced insulin resistance in Ay transgenic mice, which are vulnerable to diabetes, is mediated by P53” . “This group showed that inhibition of P53 activity, either by siRNA knockdown in cells or by TP53 gene knockout in mice, reduced senescence and instigated decreased inflammatory cytokine expression in the adipose tissue of mice, eventually preventing them from developing insulin resistance” . “The P53 codon 72 single-nucleotide polymorphism (Arg 72 Pro) has been associated with the onset of type 2 diabetes” . “In a study using a murine model of Arg 72 Pro, obesity, non-alcoholic fatty liver disease (NAFLD), and diabetes were reported in Arg-genotype mice administered with a high-fat diet” . “Furthermore, relationships between P53 downstream regulatory genes observed among CDKN1A, TNF, and Niemann-Pick C1-Like 1 (NPC1L1) (plays a role in cholesterol metabolism)” . Proper regulation of the MDM2-P53 axis is essential to prevent tumorigenesis and various metabolic diseases. “Using a lipodystrophy mouse model, Liu and his colleagues showed that chronic activation of P53 by deleting MDM2 not only causes adipocyte senescence but also apoptosis, leading to progressive lipodystrophy” . “This model exhibited various metabolic defects, reduced exercise capacity, multiorgan senescence, and shorter life span” .
The genome sequencing of cancer has revealed that 42% of cases across 12 tumour types bear mutant TP53  but taken note that the TP53 mutation rate also varies across tumour types. “Indeed, P53 is the most commonly mutated gene in some of the most difficult-to-treat cancers such as lung cancer (squamous and small-cell types) , triple-negative breast cancer , high-grade serous ovarian cancer  and esophageal (squamous type) cancer” . “In these cancer types. P53 is mutated in atleast 80% of cases” [163, 226,227,228,229]. “Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 mutations, first described by Li and Fraumeni in the year 1969” . “Patients who develop this syndrome are at increased risk of multiple primary tumours, including breast cancer, soft tissue sarcoma, brain tumours, osteosarcoma, and adrenocortical carcinoma” . Furthermore, “patients with this syndrome can also develop other cancers, including ovarian, gastrointestinal, pancreatic, genitourinary, skin, thyroid, prostate, and lung, as well as leukaemia, lymphoma, and neuroblastoma” .
“Numerous studies have shown that there is a substantial increase in P53 level and activity in neurodegenerative diseases, and it seems to be a common finding” . “In Alzheimer’s disease (AD), increased levels of P53 were seen in various parts of the patient’s brain  when compared with healthy patient’s brains. Different animal models of AD also showed an elevation in P53 levels in affected neurons” . Increased P53 levels resulted in increased sensitivity of neurons to various stressors and underwent apoptotic death . “In Parkinson’s disease (PD), the same phenomenon of increased P53 level and activity was observed in PD patient’s brains as well as in PD animal models” . This increased levels, and activity of P53 was associated with neuronal death and enhanced inflammatory cytokine levels . “A substantially higher level of P53 was also detected in the affected brain areas of Huntington disease (HD) patients and HD animal models  as well as in cells overexpressing mutated huntingtin” . A similar phenomenon observed in AD and PD that increased P53 levels was associated with DNA damage, activated cellular stress response, and apoptosis . “Various series of experiments on P53+/+, P53+/- and P53-/- mice transgenic for mutant huntingtin (mHtt) proved a causal role of P53 in HD” [237, 239]. “In this experiment, the genetic deletion of P53 not only reduced the cellular marks of mHtt expression but also protected against neuronal degeneration and improved some of the neurobehavioral defects caused by HD” [237, 239]. “An interesting observation was that even though P53 ablation did not prevent the formation of mHtt containing inclusions, P53-/- mice had lower mHtt level and increased aggregate load resulting in a milder disease phenotype” .
“Various experimental studies support the crucial role of P53 in the pathological process of acute kidney injury (AKI) and post-AKI repair of the kidney. Dagher and colleagues in 2003 first described the role of P53 in renal-ischemic-reperfusion injury (IRI) in a rat model” . “They showed that renal ischemic reperfusion-induced P53 expression in renal medulla over 24 hours postal ischemic reperfusion and pifithrin-α induced chemical inhibition of P53 activity at the time of renal ischemia inhibited tubular cell apoptosis and simultaneously resulted in renal functional protection from IRI” . “Molitoris et al. demonstrated that inhibition of P53 by short interfering RNA (siRNA), which was administered at 4 hours intravenously after renal ischemia and primarily uptaken by renal proximal tubule epithelial cells (RPTECs) within the kidney, protected against apoptosis and renal function impairment” . “Zhang and colleagues demonstrated that definite removal of the TP53 gene from proximal renal tubules protected against IRI in the kidney” . An important observation was that the deletion of P53 from other renal tubules segments was ineffective . The above studies altogether suggest a pathological role of renal tubular cell P53 in IRI.
Various studies indicate that P53 plays a protective role against various systemic autoimmune diseases by inhibiting the production of cytokine and reducing the number of pathogenic cells. “In a meta-analysis report, they have shown that TP53 codon 72 polymorphism may confer susceptibility to systemic lupus erythematosus (SLE) in Asians but not in Europeans. In contrast, there was no association between TP53 codon 72 polymorphism and rheumatoid arthritis (RA) in all study subjects” . Conversely, Macchioni et al. reported an association between the TP53 codon 72 polymorphism and joint erosion in RA . Also, Chen et al. have shown that patients with Hashimoto’s thyroiditis displayed a higher ratio of arginine homozygosity at TP53 codon 72 than healthy subjects . The precise mechanisms of how P53 protects against the development of autoimmune diseases remains unclear.
In this review, we have attempted to present a comprehensive overview of some of the P53 functions by discussing the various mechanism of P53, focusing on P53-mediated DNA damage response, and P53 role in different cellular processes like DNA repair mechanism, apoptosis, autophagy, and metabolism. We have also put some light on various P53-reactivation strategies that hold great importance in cancer therapy in the future as many small molecules are under investigation. We have also discussed how P53 levels change in various diseases. In addition to its function as guardian of the genome under various cellular stress, numerous studies suggest that P53 is allied with many other physiological processes and also different pathological processes. Following several decades of research, the complete role of P53 remains unclear. Owing to a vast and variety of P53 regulatory mechanisms and their collaboration in triggering specific responses remains an open area for research.
Availability of data and materials
This article is a review article and does not need any data and materials.
- TP53 :
Tumour protein 53
Mouse double minute 2 homologue protein
Nuclear export signal
Alternative reading frame
- DDB2 :
Damage specific DNA-binding protein 2
- XPC :
XPC complex subunit, DNA damage recognition and repair factor
- CDKN1A :
Cyclin-dependent kinase inhibitor 1
- GADD45A :
Growth arrest and DNA damage inducible alpha
- BBC3 :
BCL2 binding component 3
- PUMA :
P53 upregulated modulator of apoptosis
- BCL-2 :
B-cell Lymphoma 2
- BAX :
BCL-2-associated X, Apoptosis regulator
TP53-induced glycolysis regulatory phosphatase
- ALDH1A3 :
Aldehyde dehydrogenase 1 family, member A3
- PPM1D :
Protein phosphatase, Mg2+/Mn2+ dependent 1D
Wild-type P53-induced phosphatase 1
Protein phosphatase 1
- APAF1 :
Apoptotic peptidase activating factor 1
PML nuclear body scaffold
- YPEL3 :
ATM serine/threonine kinase
ATR serine/threonine kinase
- CHEK1 or CHEK2:
Checkpoint kinase 1 or 2
RB transcriptional corepressor 1
H2A.X variant histone
14-3-3 Phospho-serine/phospho-threonine binding proteins
Cell division control protein 2 homologue
- P21CIP1 :
Cyclin-dependent kinase inhibitor 1
- P16 INK4A:
A protein encoded by the gene CDKN2A (Cyclin-dependent kinase inhibitor 2A)
- SERPINE1 :
Serpin family E member 1
- PAI-1 :
Plasminogen activator inhibitor-1
Tripartite motif-containing protein superfamily
Senescence-associated secretory phenotype
Tumour necrosis factor alpha
Homologous recombination repair
Cyclobutane pyrimidine dimers
(6-4) Pyrimidine-pyrimidone photoproducts
RNA polymerase II
Ribonucleotide Reductase Regulatory TP53 Inducible Subunit M2B
Proliferating Cell Nuclear Antigen
DNA polymerase eta
Xeroderma pigmentosum variant
Translesion synthesis polymerases
FS-7-associated surface antigen
TNF superfamily member 10
TNF-related apoptosis-inducing ligand
Tumour necrosis factor (TNF)-receptor superfamily member 10a
Tumour necrosis factor (TNF)-receptor superfamily member 10b
TNF receptor superfamily member 1A
Mitochondrial outer membrane permeabilization
BCL2 antagonist/killer 1
- PMAIP1 :
Phorbol-12-myristate-13-acetate-induced protein 1
- BBC3 :
BCL-2-binding component 3
- BCL2L1 :
BCL2 like 1
- AEN :
- CERS5 :
Ceramide Synthase 5
- CERS6 :
Ceramide Synthase 6
- TRIAP1 :
TP53 Regulated Inhibitor of Apoptosis 1
- DRAM1 :
DNA damage-regulated autophagy modulator 1
- ULK1 :
UNC-51-like autophagy-activating kinase 1
- TSC2 :
Tuberous Sclerosis Complex subunit 2
- PTEN :
Phosphatase and tensin homologue
- PRKAA2 :
Protein kinase AMP-activated catalytic subunit alpha 2
Mechanistic target of rapamycin kinase
- BNIP3 :
BCL2 Interacting Protein 3
- DAPK-1 :
Death-associated protein kinase 1
- MAP 1 LC3A:
Microtubule-associated protein 1A/1B-light chain 3 alpha
- MAP1 B:
Microtubule-associated protein 1B
Solute carrier family 2 member 1
Glucose transporter type 1
Solute carrier family 2 member 4
Glucose transporter type 4
Solute carrier family 2 member 3
Glucose transporter type 3
Nuclear factor kappa-light-chain-enhancer of activated B cells
TP53-inducible glycolysis and apoptosis regulator
- RRAD :
Ras-related glycolysis inhibitor and calcium channel regulator
- PDK2 :
Pyruvate dehydrogenase kinase 2
- PDH :
- PRKN :
Parkin RBR E3 ubiquitin-protein ligase
Pyruvate dehydrogenase E1 subunit alpha 1
Malonyl-CoA-acyl carrier protein transacylase
Synthesis of cytochrome c oxidase 2
Electron transport chain
- AIFM1 :
Apoptosis-inducing factor mitochondria associated 1
Pentose phosphate pathway
AKT serine/threonine kinase 1
- PANK1 :
- G6PC :
Glucose-6-phosphatase catalytic subunit
- PCK1 :
- SIRT6 :
Forkhead box protein O1
Fatty acid oxidation
- CROT :
- CPTA1 :
Carnitine palmitoyltransferase 1A
- CPT1C :
Carnitine palmitoyltransferase 1C
- LPIN1 :
Fatty acid synthesis
Sterol regulatory element-binding proteins
Mono-unsaturated fatty acids
- SLC7A3 :
Solute carrier family 7 member 3
- ATF4 :
Activating transcription factor 4
Levine A, Oren M. The first 30 years of P53: growing ever more complex. Nature Reviews Cancer [Internet]. (2009) [cited 11 may 2020]; 9(10):749-758Available from https://doi.org/https://doi.org/10.1038/nrc2723
Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J et al (2016) [cited 11 may 2020]; 37(9):865-876Available from https://doi.org/https://doi.org/10.1002/humu.23035
Vousden K, Prives C. Blinded by the light: the growing complexity of P53. Cell [Internet]. (2009) 137(3):413-431Available from https://doi.org/https://doi.org/10.1016/j.cell.2009.04.037
Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human P53-regulated genes. Nature Reviews Molecular Cell Biology [Internet]. (2008) [cited 11 may 2020]; 9(5):402-412Available from https://doi.org/https://doi.org/10.1038/nrm2395
Levine A. P53, the cellular gatekeeper for growth and division. Cell [Internet]. (1997) [cited 11 may 2020]; 88(3):323-331Available from https://doi.org/https://doi.org/10.1016/s0092-8674(00)81871-1
Census FM, evaluation of P53 target genes. Oncogene [Internet]. (2017) [cited 11 may 2020]; 36(28):3943-3956Available from https://doi.org/https://doi.org/10.1038/onc.2016.502
Lane D, Madhumalar A, Lee A, Tay B, Verma C, Brenner S et al (2011) [cited 11 may 2020]; 10(24):4272-4279Available from https://doi.org/https://doi.org/10.4161/cc.10.24.18567
Belyi V, Ak P, Markert E, Wang H, Hu W, Puzio-Kuter A et al (2009) [cited 11 may 2020]; 2(6):a001198-a001198Available from https://doi.org/https://doi.org/10.1101/cshperspect.a001198
Jain A, Barton M. P53: emerging roles in stem cells, development and beyond. Development [Internet]. (2018) [cited 23 July 2020];145(8):dev158360Available from https://doi.org/https://doi.org/10.1242/dev.158360
Lin J, Chen J, Elenbaas B, Levine A. Several hydrophobic amino acids in the P53 amino-terminal domain are required for transcriptional activation, binding to MDM-2, and the adenovirus 5 E1B 55-kD protein. Genes & Development [Internet]. (1994) [cited 11 may 2020]; 8(10):1235-1246Available from https://doi.org/https://doi.org/10.1101/gad.8.10.1235
Chen X, Farmer G, Zhu H, Prywes R, Prives C. Cooperative DNA binding of P53 with TFIID (TBP): a possible mechanism for transcriptional activation. Genes & Development [Internet]. 1993 [cited 11 may 2020]; 7(10):1837-1849. Available from: https://doi.org/https://doi.org/10.1101/gad.7.10.1837
Thut C, Chen J, Klemm R, Tjian R. P53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science [Internet]. (1995) 267(5194):100-104Available from https://doi.org/https://doi.org/10.1126/science.7809597
Walker K, Levine A. Identification of a novel P53 functional domain that is necessary for efficient growth suppression. Proceedings of the National Academy of Sciences [Internet]. (1996) [cited 11 may 2020];93(26):15335-15340Available from https://doi.org/https://doi.org/10.1073/pnas.93.26.15335
Bargonetti J, Manfredi J, Chen X, Marshak D, Prives C. A proteolytic fragment from the central region of P53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant P53 protein. Genes & Development [Internet]. (1993) [cited 11 may 2020]; 7(12b):2565-2574Available from https://doi.org/https://doi.org/10.1101/gad.7.12b.2565
Pavletich N, Chambers K, Pabo C. The DNA-binding domain of P53 contains the four conserved regions and the major mutation hot spots. Genes & Development [Internet]. 1993 [cited 11 may 2020]; 7(12b):2556-2564. Available from: https://doi.org/https://doi.org/10.1101/gad.7.12b.2556
El-Deiry W, Kern S, Pietenpol J, Kinzler K, Vogelstein B. Definition of a consensus binding site for P53. Nature Genetics [Internet]. (1992) [cited 11 may 2020];1(1):45-49Available from https://doi.org/https://doi.org/10.1038/ng0492-45
Cho Y, Gorina S, Jeffrey P, Pavletich N. Crystal structure of a P53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science [Internet]. (1994) [cited 11 may 2020];265(5170):346-355Available from https://doi.org/https://doi.org/10.1126/science.8023157
Jeffrey P, Gorina S, Pavletich N. Crystal structure of the tetramerization domain of the P53 tumor suppressor at 1.7 angstroms. Science [Internet]. 1995;267(5203):1498-1502. Available from: https://science.sciencemag.org/content/267/5203/1498
McCoy M Hydrophobic side-chain size is a determinant of the three-dimensional structure of the P53 oligomerization domain. The EMBO Journal [Internet]. 1997;16(20):6230-6236. Available from https://doi.org/https://doi.org/10.1093/emboj/16.20.6230
Stommel J. A leucine-rich nuclear export signal in the P53 tetramerization domain: regulation of subcellular localization and P53 activity by NES masking. The EMBO Journal [Internet]. (1999) [cited 11 may 2020];18(6):1660-1672Available from https://doi.org/https://doi.org/10.1093/emboj/18.6.1660
Fischer N, Prodeus A, Malkin D, Gariépy J. P53 oligomerization status modulates cell fate decisions between growth, arrest, and apoptosis. Cell Cycle [Internet]. (2016) [cited 11 May 2020];15(23):3210-3219Available from https://doi.org/https://doi.org/10.1080/15384101.2016.1241917
Bourdon J. P53 isoforms can regulate P53 transcriptional activity. Genes & Development [Internet]. (2005) [cited 11 may 2020];19(18):2122-2137Available from https://doi.org/https://doi.org/10.1101/gad.1339905
Dai C, Gu W. P53 post-translational modification: deregulated in tumorigenesis. Trends in Molecular Medicine [Internet]. (2010) [cited 11 may 2020];16(11):528-536Available from https://doi.org/https://doi.org/10.1016/j.molmed.2010.09.002
Zhang Y, Xiong Y, Yarbrough W. ARF promotes MDM2 degradation and stabilizes P53: ARF-INK4a locus deletion impairs both the Rb and P53 tumor suppression pathways. Cell [Internet]. (1998) [cited 11 may 2020];92(6):725-734Available from https://doi.org/https://doi.org/10.1016/s0092-8674(00)81401-4
Genome EC, Stability Requires P53. Cold spring harbor perspectives in medicine [Internet]. (2016) [cited 23 July 2020];6(6):a026096Available from https://doi.org/https://doi.org/10.1101/cshperspect.a026096
Kruiswijk F, Labuschagne C, Vousden K. P53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nature Reviews Molecular Cell Biology [Internet]. (2015) [cited 11 may 2020];16(7):393-405Available from https://doi.org/https://doi.org/10.1038/nrm4007
Hafner A, Bulyk M, Jambhekar A, Lahav G. The multiple mechanisms that regulate P53 activity and cell fate. Nature Reviews Molecular Cell Biology [Internet]. (2019) [cited 11 may 2020];20(4):199-210Available from https://doi.org/https://doi.org/10.1038/s41580-019-0110-x
Mirza A, Wu Q, Wang L, McClanahan T, Bishop W, Gheyas F et al (2003) [cited 11 may 2020];22(23):3645-3654Available from https://doi.org/https://doi.org/10.1038/sj.onc.1206477
Purvis J, Karhohs K, Mock C, Batchelor E, Loewer A, Lahav G. P53 dynamics control cell fate. Science [Internet]. (2012) [cited 11 may 2020];336(6087):1440-1444Available from https://doi.org/https://doi.org/10.1126/science.1218351
El-Deiry W. WAF1, a potential mediator of P53 tumor suppression. Cell [Internet]. (1993) [cited 11 may 2020];75(4):817-825Available from https://doi.org/https://doi.org/10.1016/0092-8674(93)90500-P
El-Deiry W. Regulation ofP53downstream genes. Seminars in Cancer Biology [Internet]. (1998) [cited 11 may 2020];8(5):345-357Available from https://doi.org/https://doi.org/10.1006/scbi.1998.0097
Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology [Internet]. 2013 [cited 11 may 2020];14(4):197-210. Available from: https://doi.org/https://doi.org/10.1038/nrm3546
Xiong Y, Hannon G, Zhang H, Casso D, Kobayashi R, Beach D. P21 is a universal inhibitor of cyclin kinases. Nature [Internet]. (1993) [cited 11 may 2020];366(6456):701-704Available from https://doi.org/https://doi.org/10.1038/366701a0
Weinberg R. The retinoblastoma protein and cell cycle control. Cell [Internet]. (1995) [cited 11 may 2020];81(3):323-330Available from https://doi.org/https://doi.org/10.1016/0092-8674(95)90385-2
Dulić V, Kaufmann W, Wilson S, Tisty T, Lees E, Harper J et al (1994) [cited 11 may 2020];76(6):1013-1023Available from https://doi.org/https://doi.org/10.1016/0092-8674(94)90379-4
Deng C, Zhang P, Wade Harper J, Elledge S, Leder P. Mice Lacking P21CIP1/WAF1 undergo normal development but are defective in G1 checkpoint control. Cell [Internet]. 1995 [cited 12 may 2020];82(4):675-684. Available from: https://doi.org/https://doi.org/10.1016/0092-8674(95)90039-x
Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer W et al (1997) [cited 12 may 2020];94(12):6048-6053Available from https://doi.org/https://doi.org/10.1073/pnas.94.12.6048
Shreeram S, Demidov O, Hee W, Yamaguchi H, Onishi N, Kek C et al (2006) [cited 12 may 2020];23(5):757-764Available from https://doi.org/https://doi.org/10.1016/j.molcel.2006.07.010
Goloudina A, Kochetkova E, Pospelova T, Demidov O. Wip1 phosphatase: between P53 and MAPK kinases pathways. Oncotarget [Internet]. 2016 [cited 12 May 2020];7(21):31563-31571. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.7325
Vogelstein B, Lane D, Levine A. Surfing the P53 network. Nature [Internet]. (2000) [cited 12 may 2020];408(6810):307-310Available from https://doi.org/https://doi.org/10.1038/35042675
Harris S, Levine A. The P53 pathway: positive and negative feedback loops. Oncogene [Internet]. 2005 [cited 12 may 2020];24(17):2899-2908. Available from: https://doi.org/https://doi.org/10.1038/sj.onc.1208615
Lakin N, Jackson S. Regulation of P53 in response to DNA damage. Oncogene [Internet]. (1999) [cited 12 may 2020];18(53):7644-7655Available from https://doi.org/https://doi.org/10.1038/sj.onc.1203015
Hermeking H, Lengauer C, Polyak K, He T, Zhang L, Thiagalingam S et al (1997) [cited 12 may 2020];1(1):3-11Available from https://doi.org/https://doi.org/10.1016/s1097-2765(00)80002-7
Taylor W, Stark G. Regulation of the G2/M transition by P53. Oncogene [Internet]. (2001) [cited 12 may 2020];20(15):1803-1815Available from https://doi.org/https://doi.org/10.1038/sj.onc.1204252
Deng Y, Chan S, Chang S. Telomere dysfunction and tumor suppression: the senescence connection. Nature Reviews Cancer [Internet]. (2008) [cited 12 may 2020];8(6):450-458Available from https://doi.org/https://doi.org/10.1038/nrc2393
Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of P21CIP1/WAF1 gene in normal diploid human fibroblasts. Science. 277(5327):831–834 https://doi.org/10.1126/science.277.5327.831
Childs B, Durik M, Baker D, van Deursen J. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature Medicine [Internet]. (2015) [cited 13 may 2020];21(12):1424-1435Available from https://doi.org/https://doi.org/10.1038/nm.4000
Childs B, Baker D, Kirkland J, Campisi J, Deursen J. Senescence and apoptosis: dueling or complementary cell fates?. EMBO reports [Internet]. 2014 [cited 13 May 2020];15(11):1139-1153. Available from: https://doi.org/https://doi.org/10.15252/embr.201439245
Sharpless N, Sherr C. Forging a signature of in vitro senescence. Nature Reviews Cancer [Internet]. (2015) [cited 13 may 2020];15(7):397-408Available from https://doi.org/https://doi.org/10.1038/nrc3960
Kortlever R, Higgins P, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of P53 in the induction of replicative senescence. Nature Cell Biology [Internet]. (2006) [cited 13 may 2020];8(8):877-884Available from https://doi.org/https://doi.org/10.1038/ncb1448
Reymond A. The tripartite motif family identifies cell compartments. The EMBO Journal [Internet]. (2001) [cited 13 may 2020];20(9):2140-2151Available from https://doi.org/https://doi.org/10.1093/emboj/20.9.2140
Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S et al (2000) [cited 13 may 2020];406(6792):207-210Available from https://doi.org/https://doi.org/10.1038/35018127
Deconstructing BO, PML-induced premature senescence. The EMBO Journal [Internet]. (2002) [cited 13 may 2020];21(13):3358-3369Available from https://doi.org/https://doi.org/10.1093/emboj/cdf341
Alcalay M, Tomassoni L, Colombo E, Stoldt S, Grignani F, Fagioli M et al (1998) [cited 13 may 2020];18(2):1084-1093Available from https://doi.org/https://doi.org/10.1128/mcb.18.2.1084
Kuilman T, Peeper D. Senescence-messaging secretome: SMS-ing cellular stress. Nature Reviews Cancer [Internet]. (2009) [cited 13 may 2020];9(2):81-94Available from https://doi.org/https://doi.org/10.1038/nrc2560
Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh D, Bolden J et al (2013) [cited 13 may 2020];153(2):449-460Available from https://doi.org/https://doi.org/10.1016/j.cell.2013.03.020
Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein R, Biton M et al (2013) [cited 13 may 2020];24(2):242-256Available from https://doi.org/https://doi.org/10.1016/j.ccr.2013.06.005
Brady C, Attardi L. P53 at a glance. Journal of Cell Science [Internet]. (2010) [cited 13 may 2020];123(15):2527-2532Available from https://doi.org/https://doi.org/10.1242/jcs.064501
Sengupta S, Harris C. P53: traffic cop at the crossroads of DNA repair and recombination. Nature Reviews Molecular Cell Biology [Internet]. (2005) [cited 13 may 2020];6(1):44-55Available from https://doi.org/https://doi.org/10.1038/nrm1546
Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama J, Burks D, Yung S et al. A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors. Cell Death & Differentiation [Internet]. 2013 [cited 13 may 2020];20(8):1089-1100. Available from: https://doi.org/https://doi.org/10.1038/cdd.2013.44
Campisi J Aging, tumor suppression and cancer: high wire-act!. Mechanisms of ageing and Development [Internet]. 2005;126(1):51-58. Available from https://doi.org/https://doi.org/10.1016/j.mad.2004.09.024
Friedberg E. How nucleotide excision repair protects against cancer. Nature Reviews Cancer [Internet]. (2001) [cited 13 may 2020];1(1):22-33Available from https://doi.org/https://doi.org/10.1038/35094000
Lieber M, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Reviews Molecular Cell Biology [Internet]. 2003 [cited 13 may 2020];4(9):712-720. Available from: https://doi.org/https://doi.org/10.1038/nrm1202
Sancar A, Lindsey-Boltz L, Ünsal-Kaçmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual Review of Biochemistry [Internet]. (2004) [cited 13 may 2020];73(1):39-85Available from https://doi.org/https://doi.org/10.1146/annurev.biochem.73.011303.073723
Bennardo N, Cheng A, Huang N, Stark J. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genetics [Internet]. (2008) [cited 13 may 2020];4(6):e1000110Available from https://doi.org/https://doi.org/10.1371/journal.pgen.1000110
Christophorou M, Ringshausen I, Finch A, Swigart L, Evan G. The pathological response to DNA damage does not contribute to P53-mediated tumor suppression. Nature [Internet]. (2006) [cited 13 may 2020];443(7108):214-217Available from https://doi.org/https://doi.org/10.1038/nature05077
Tan T, Chu G. P53 binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. Molecular and Cellular Biology [Internet]. (2002) [cited 13 may 2020];22(10):3247-3254Available from https://doi.org/https://doi.org/10.1128/mcb.22.10.3247-3254.2002
Adimoolam S, Ford J P53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proceedings of the National Academy of Sciences [Internet]. 2002;99(20):12985-12990. Available from https://doi.org/10.1073/pnas.202485699
Hoeijmakers J. DNA damage, aging, and cancer. New England Journal of Medicine [Internet]. (2009) [cited 13 may 2020];361(15):1475-1485Available from https://doi.org/https://doi.org/10.1056/NEJMra0804615
Bergink S, Jaspers N, Vermeulen W. Regulation of UV-induced DNA damage response by ubiquitylation. DNA Repair [Internet]. (2007) [cited 13 may 2020];6(9):1231-1242Available from https://doi.org/https://doi.org/10.1016/j.dnarep.2007.01.012
Hanawalt P, Spivak G. Transcription-coupled DNA repair: two decades of progress and surprises. Nature Reviews Molecular Cell Biology [Internet]. 2008 [cited 13 may 2020];9(12):958-970. Available from: https://doi.org/https://doi.org/10.1038/nrm2549
Lagerwerf S, Vrouwe M, Overmeer R, Fousteri M, Mullenders L. DNA damage response and transcription. DNA Repair [Internet]. (2011) [cited 13 may 2020];10(7):743-750Available from https://doi.org/https://doi.org/10.1016/j.dnarep.2011.04.024
Sugasawa K, Ng J, Masutani C, Iwai S, van der Spek P, Eker A et al (1998) [cited 13 may 2020];2(2):223-232Available from https://doi.org/https://doi.org/10.1016/s1097-2765(00)80132-x
Volker M, Moné M, Karmakar P, van Hoffen A, Schul W, Vermeulen W et al (2001) [cited 13 may 2020];8(1):213-224Available from https://doi.org/https://doi.org/10.1016/s1097-2765(01)00281-7
Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K et al (2000) [cited 13 may 2020];404(6773):42-49Available from https://doi.org/https://doi.org/10.1038/35003506
Moldovan G, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell [Internet]. 2007 [cited 13 may 2020];129(4):665-679. Available from: https://doi.org/https://doi.org/10.1016/j.cell.2007.05.003
Morris GF, Mathews MB (1989) Regulation of proliferating cell nuclear antigen during the cell cycle. J Biol Chem 264(23):13856–13864
Garg P, Burgers P. DNA polymerases that propagate the eukaryotic DNA replication fork. Critical Reviews in Biochemistry and Molecular Biology [Internet]. (2005) [cited 13 may 2020];40(2):115-128Available from https://doi.org/https://doi.org/10.1080/10409230590935433
Liu G, Chen X. DNA polymerase η, the product of the xeroderma pigmentosum variant gene and a target of P53, modulates the DNA damage checkpoint and P53 activation. Molecular and Cellular Biology [Internet]. (2006) [cited 13 may 2020];26(4):1398-1413Available from https://doi.org/https://doi.org/10.1128/MCB.26.4.1398-1413.2006
Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M et al (1999) [cited 13 may 2020];399(6737):700-704Available from https://doi.org/https://doi.org/10.1038/21447
Menck C, Munford V. DNA repair diseases: what do they tell us about cancer and aging?. Genetics and Molecular Biology [Internet]. (2014) [cited 13 may 2020];37(1 suppl 1):220-233Available from https://doi.org/https://doi.org/10.1590/s1415-47572014000200008
Friedberg E, Lehmann A, Fuchs R. Trading places: how do DNA polymerases switch during translesion DNA synthesis?. Molecular Cell [Internet]. (2005) [cited 13 may 2020];18(5):499-505Available from https://doi.org/https://doi.org/10.1016/j.molcel.2005.03.032
Knudson C, Tung K, Tourtellotte W, Brown G, Korsmeyer S. BAX-deficient mice with lymphoid hyperplasia and male germ cell death. Science [Internet]. (1995) [cited 13 may 2020];270(5233):96-99Available from https://doi.org/https://doi.org/10.1126/science.270.5233.96
Eischen C, Roussel M, Korsmeyer S, Cleveland J. BAX loss impairs Myc-induced apoptosis and circumvents the selection of P53 mutations during Myc-mediated lymphomagenesis. Molecular and Cellular Biology [Internet]. (2001) [cited 13 may 2020];21(22):7653-7662Available from https://doi.org/https://doi.org/10.1128/MCB.21.22.7653-7662.2001
Luke J, van de Wetering C, Knudson C. Lymphoma development in BAX transgenic mice is inhibited by BCL-2 and associated with chromosomal instability. Cell Death & Differentiation [Internet]. (2003) [cited 13 may 2020];10(6):740-748Available from https://doi.org/https://doi.org/10.1038/sj.cdd.4401233
Ke F, Vanyai H, Cowan A, Delbridge A, Whitehead L, Grabow S et al Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell [Internet]. 2018 [cited 13 may 2020];173(5):1217-1230.e17. Available from https://doi.org/https://doi.org/10.1016/j.cell.2018.04.036
Los M, CrAEN M, Penning L, Schenk H, Westendorp M, Baeuerle P et al (1995) [cited 13 may 2020];375(6526):81-83Available from https://doi.org/https://doi.org/10.1038/375081a0
Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J (1993) Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 75(4):653–660 https://doi.org/https://doi.org/10.1016/0092-8674(93)90486-A
Taylor R, Cullen S, Martin S. Apoptosis: controlled demolition at the cellular level. Nature Reviews Molecular Cell Biology [Internet]. (2008) [cited 13 may 2020];9(3):231-241Available from https://doi.org/https://doi.org/10.1038/nrm2312
Tait S, Green D. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature Reviews Molecular Cell Biology [Internet]. 2010 [cited 13 may 2020];11(9):621-632. Available from: https://doi.org/https://doi.org/10.1038/nrm2952
Yonish-Rouach E, Resnftzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type P53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature [Internet]. 1991 [cited 13 may 2020];352(6333):345-347. Available from: https://doi.org/https://doi.org/10.1038/352345a0
Chipuk J, Green D. Dissecting P53-dependent apoptosis. Cell Death & Differentiation [Internet]. 2006 [cited 13 may 2020];13(6):994-1002. Available from: https://doi.org/https://doi.org/10.1038/sj.cdd.4401908
Yu J, Zhang L. No PUMA, no death. Cancer Cell [Internet]. 2003 [cited 13 may 2020];4(4):248-249. Available from: https://doi.org/https://doi.org/10.1016/s1535-6108(03)00249-6
Green D, Kroemer G. Cytoplasmic functions of the tumor suppressor P53. Nature [Internet]. (2009) [cited 13 may 2020];458(7242):1127-1130Available from https://doi.org/https://doi.org/10.1038/nature07986
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al (2003) [cited 13 may 2020];11(3):577-590Available from https://doi.org/https://doi.org/10.1016/s1097-2765(03)00050-9
Follis A, Llambi F, Ou L, Baran K, Green D, Kriwacki R. The DNA-binding domain mediates both nuclear and cytosolic functions of P53. Nature Structural & Molecular Biology [Internet]. 2014 [cited 13 may 2020];21(6):535-543. Available from: https://doi.org/https://doi.org/10.1038/nsmb.2829
Chipuk J, Moldoveanu T, Llambi F, Parsons M, Green D. The BCL-2 family reunion. Molecular Cell [Internet]. 2010 [cited 13 may 2020];37(3):299-310. Available from: https://doi.org/https://doi.org/10.1016/j.molcel.2010.01.025
Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C et al (2006) [cited 13 may 2020];281(13):8600-8606Available from https://doi.org/https://doi.org/10.1074/jbc.M507611200
Karbowski M, Norris K, Cleland M, Jeong S, Youle R. Role of BAX and BAK in mitochondrial morphogenesis. Nature [Internet]. (2006) [cited 13 may 2020];443(7112):658-662Available from https://doi.org/https://doi.org/10.1038/nature05111
Robles AI, Bemmels NA, Foraker AB, Harris CC (2001) APAF-1 is a transcriptional target of P53 in DNA damage-induced apoptosis. Cancer Res 61(18):6660–6664 https://cancerres.aacrjournals.org/content/61/18/6660
Rozenfeld-Granot G, Krishnamurthy J, Kannan K, Toren A, Amariglio N, Givol D et al A positive feedback mechanism in the transcriptional activation of Apaf-1 by P53 and the coactivator Zac-1. Oncogene [Internet]. 2002;21(10):1469-1476. Available from https://doi.org/https://doi.org/10.1038/sj.onc.1205218
Kawase T, Ichikawa H, Ohta T, Nozaki N, Tashiro F, Ohki R et al (2008) [cited 13 may 2020];27(27):3797-3810Available from https://doi.org/https://doi.org/10.1038/onc.2008.32
Fekry B, Jeffries K, Esmaeilniakooshkghazi A, Ogretmen B, Krupenko S, Krupenko N. CERS6Is a novel transcriptional target of P53 protein activated by non-genotoxic stress. Journal of Biological Chemistry [Internet]. (2016) [cited 13 may 2020];291(32):16586-16596Available from https://doi.org/https://doi.org/10.1074/jbc.M116.716902
Panjarian S, Kozhaya L, Arayssi S, Yehia M, Bielawski J, Bielawska A et al (2008) [cited 13 may 2020];86(1-4):41-48Available from https://doi.org/https://doi.org/10.1016/j.prostaglandins.2008.02.004
Park W, Nakamura Y. P53CSV, a novel P53-inducible gene involved in the P53-dependent cell-survival pathway. Cancer Research [Internet]. (2005) [cited 13 may 2020];65(4):1197-1206Available from https://doi.org/https://doi.org/10.1158/0008-5472.CAN-04-3339
Tasdemir E, Maiuri M, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M et al (2008) [cited 13 may 2020];10(6):676-687Available from https://doi.org/https://doi.org/10.1038/ncb1730
Choundhury S, Kolukula V, Preet A, Albanese C, Avantaggiati M. Dissecting the pathways that destabilize mutant P53: The proteasome or autophagy?. Cell Cycle [Internet]. (2013) [cited 13 may 2020];12(7):1022-1029Available from https://doi.org/https://doi.org/10.4161/cc.24128
Kenzelmann Broz D, Spano Mello S, Bieging K, Jiang D, Dusek R, Brady C et al (2013) [cited 13 may 2020];27(9):1016-1031Available from https://doi.org/https://doi.org/10.1101/gad.212282.112
Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison P et al (2006) [cited 13 may 2020];126(1):121-134Available from https://doi.org/https://doi.org/10.1016/j.cell.2006.05.034
Gao W, Shen Z, Shang L, Wang X. Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor P53 contributes to DNA-damage-induced cell death. Cell Death & Differentiation [Internet]. (2011) [cited 13 may 2020];18(10):1598-1607Available from https://doi.org/https://doi.org/10.1038/cdd.2011.33
Kenzelmann Broz D, Attardi L. TRP53 activates a global autophagy program to promote tumor suppression. Autophagy [Internet]. (2013) [cited 13 may 2020];9(9):1440-1442Available from https://doi.org/https://doi.org/10.4161/auto.25833
Arico S, Petiot A, Bauvy C, Dubbelhuis P, Meijer A, Codogno P et al (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276(38):35243–35246
Feng Z, Zhang H, Levine A, Jin S. The coordinate regulation of the P53 and mTOR pathways in cells. Proceedings of the National Academy of Sciences [Internet]. (2005) [cited 13 may 2020];102(23):8204-8209Available from https://doi.org/https://doi.org/10.1073/pnas.0502857102
Lee J, Budanov A, Park E, Birse R, Kim T, Perkins G et al (2010) [cited 13 may 2020];327(5970):1223-1228Available from https://doi.org/https://doi.org/10.1126/science.1182228
Budanov A, Karin M. P53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling. Cell [Internet]. (2008) [cited 13 may 2020];134(3):451-460Available from https://doi.org/https://doi.org/10.1016/j.cell.2008.06.028
Crighton D, Wilkinson S, Ryan K. DRAM links autophagy to P53 and programmed cell death. Autophagy [Internet]. (2007) [cited 13 may 2020];3(1):72-74Available from https://doi.org/https://doi.org/10.4161/auto.3438
Wang E, Gang H, Aviv Y, Dhingra R, Margulets V, Kirshenbaum L P53 mediates autophagy and cell death by a mechanism contingent on BNIP3. Hypertension [Internet]. 2013;62(1):70-77. Available from https://doi.org/https://doi.org/10.1161/HYPERTENSIONAHA.113.01028
Yee K, Wilkinson S, James J, Ryan K, Vousden K. PUMA- and BAX-induced autophagy contributes to apoptosis. Cell Death & Differentiation [Internet]. (2009) [cited 13 may 2020];16(8):1135-1145Available from https://doi.org/https://doi.org/10.1038/cdd.2009.28
Pattingre S, Tassa A, Qu X, Garuti R, Liang X, Mizushima N et al (2005) [cited 13 may 2020];122(6):927-939Available from https://doi.org/https://doi.org/10.1016/j.cell.2005.07.002
Pimkina J, Humbey O, Zilfou J, Jarnik M, Murphy M. ARF induces autophagy by virtue of interaction with Bcl-xl. Journal of Biological Chemistry [Internet]. (2008) [cited 13 may 2020];284(5):2803-2810Available from https://doi.org/https://doi.org/10.1074/jbc.M804705200
Balaburski G, Hontz R, Murphy M. P53 and ARF: unexpected players in autophagy. Trends in Cell Biology [Internet]. (2010) [cited 13 may 2020];20(6):363-369Available from https://doi.org/https://doi.org/10.1016/j.tcb.2010.02.007
Gade P, Manjegowda S, Nallar S, Maachani U, Cross A, Kalvakolanu D. Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1. Molecular and Cellular Biology [Internet]. (2014) [cited 13 may 2020];34(21):4033-4048Available from https://doi.org/https://doi.org/10.1128/MCB.00397-14
Zalckvar E, Berissi H, Eisenstein M, Kimchi A. Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with BCL-2 and Bcl-XL. Autophagy [Internet]. (2009) [cited 13 may 2020];5(5):720-722Available from https://doi.org/https://doi.org/10.4161/auto.5.5.8625
Harrison B, Kraus M, Burch L, Stevens C, Craig A, Gordon-Weeks P et al (2008) DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. J Biol Chem 283(15):9999–10014
Jones R, Plas D, Kubek S, Buzzai M, Mu J, Xu Y et al AMP-activated protein kinase induces a P53-dependent metabolic checkpoint. Molecular Cell [Internet]. 2005;18(3):283-293. Available from https://doi.org/https://doi.org/10.1016/j.molcel.2005.03.027
Reid M, Wang W, Rosales K, Welliver M, Pan M, Kong M. The B55α subunit of PP2A drives a P53-dependent metabolic adaptation to glutamine deprivation. Molecular Cell [Internet]. 2013 [cited 13 may 2020];50(2):200-211. Available from: https://doi.org/https://doi.org/10.1016/j.molcel.2013.02.008
Maddocks O, Berkers C, Mason S, Zheng L, Blyth K, Gottlieb E et al (2012) [cited 13 may 2020];493(7433):542-546Available from https://doi.org/https://doi.org/10.1038/nature11743
Tarangelo A, Magtanong L, Bieging-Rolett K, Li Y, Ye J, Attardi L et al (2018) [cited 13 may 2020];22(3):569-575Available from https://doi.org/https://doi.org/10.1016/j.celrep.2017.12.077
Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, Lin M, Yu H, Liu L, Levine AJ, Hu W (2013) Tumour-associated mutant P53 drives the Warburg effect. Nat Commun 4(1):1–5 https://doi.org/https://doi.org/10.1038/ncomms3935
Kawauchi K, Araki K, Tobiume K, Tanaka N. P53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nature Cell Biology [Internet]. (2008) [cited 13 may 2020];10(5):611-618Available from https://doi.org/https://doi.org/10.1038/ncb1724
Ros S, Flöter J, Kaymak I, Da Costa C, Houddane A, Dubuis S et al 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for P53-null cancer cells. Oncogene [Internet]. 2017;36(23):3287-3299. Available from https://doi.org/https://doi.org/10.1038/onc.2016.477
Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65(1):177–185 https://cancerres.aacrjournals.org/content/65/1/177
Zhang C, Liu J, Wu R, Liang Y, Lin M, Liu J et al. Tumor suppressor P53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD. Oncotarget [Internet]. 2014 [cited 13 May 2020];5(14):5535-5546. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.2137
Contractor T, Harris C. P53 negatively regulates transcription of the pyruvate dehydrogenase kinase PDK2. Cancer Research [Internet]. (2011) [cited 13 may 2020];72(2):560-567Available from https://doi.org/https://doi.org/10.1158/0008-5472.CAN-11-1215
Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel P53 target gene regulating energy metabolism and antioxidant function. Proceedings of the National Academy of Sciences [Internet]. (2010) [cited 13 may 2020];107(16):7455-7460Available from https://doi.org/https://doi.org/10.1073/pnas.1001006107
Suzuki S, Tanaka T, Poyurovsky M, Nagano H, Mayama T, Ohkubo S et al Phosphate-activated glutaminase (GLS2), a P53-inducible regulator of glutamine metabolism and reactive oxygen species. Proceedings of the National Academy of Sciences [Internet]. 2010;107(16):7461-7466. Available from https://doi.org/https://doi.org/10.1073/pnas.1002459107
Boidot R, Vegran F, Meulle A, Le Breton A, Dessy C, Sonveaux P et al (2011) [cited 13 may 2020];72(4):939-948Available from https://doi.org/https://doi.org/10.1158/0008-5472.CAN-11-2474
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) P53 regulates mitochondrial respiration. Science. 312(5780):1650–1653 https://doi.org/10.1126/science.1126863
Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M et al Regulation of AIF expression by P53. Cell Death & Differentiation [Internet]. 2006;13(12):2140-2149. Available from https://doi.org/10.1038/sj.cdd.4401965
Kitamura N, Nakamura Y, Miyamoto Y, Miyamoto T, Kabu K, Yoshida M et al (2011) [cited 13 may 2020];6(1):e16060Available from https://doi.org/https://doi.org/10.1371/journal.pone.0016060
Sahin E, Colla S, Liesa M, Moslehi J, Müller F, Guo M et al (2011) [cited 13 may 2020];470(7334):359-365Available from https://doi.org/https://doi.org/10.1038/nature09787
Lee P, Vousden K, Cheung E TIGAR, TIGAR, burning bright. Cancer & Metabolism [Internet]. 2014;2(1):1. Available from https://doi.org/https://doi.org/10.1186/2049-3002-2-1
Duan L, Perez R, Chen L, Blatter L, Maki C. P53 promotes AKT and SP1-dependent metabolism through the pentose phosphate pathway that inhibits apoptosis in response to Nutlin-3a. Journal of Molecular Cell Biology [Internet]. (2018) [cited 13 may 2020];10(4):331-340Available from https://doi.org/https://doi.org/10.1093/jmcb/mjx051
Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M et al (2011) [cited 13 may 2020];13(3):310-316Available from https://doi.org/https://doi.org/10.1038/ncb2172
Goldstein I, Yizhak K, Madar S, Goldfinger N, Ruppin E, Rotter V. P53 promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose production. Cancer & Metabolism [Internet]. (2013) [cited 13 may 2020];1(1)Available from https://doi.org/https://doi.org/10.1186/2049-3002-1-9
Harami-Papp H, Pongor L, Munkácsy G, Horváth G, Nagy Á, Ambrus A et al. TP53 mutation hits energy metabolism and increases glycolysis in breast cancer. Oncotarget [Internet] 2016;7(41):67183-67195. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.11594
Wang S, Yu G, Jiang L, Li T, Lin Q, Tang Y et al (2013) [cited 13 may 2020];12(5):753-761Available from https://doi.org/https://doi.org/10.4161/cc.23597
Prokesch A, Graef F, Madl T, Kahlhofer J, Heidenreich S, Schumann A et al. Liver P53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. FASEB J [Internet]. 2016;31(2):732-742. Available from: https://doi.org/https://doi.org/10.1096/fj.201600845R
Zhang P, Tu B, Wang H, Cao Z, Tang M, Zhang C et al. Tumor suppressor P53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci [Internet]. 2014;111(29):10684-10689. Available from: https://doi.org/https://doi.org/10.1073/pnas.1411026111
Berkers C, Maddocks O, Cheung E, Mor I, Vousden K. Metabolic regulation by P53 family members. Cell Metabolism [Internet]. (2013) [cited 13 may 2020];18(5):617-633Available from https://doi.org/https://doi.org/10.1016/j.cmet.2013.06.019
Goldstein I, Ezra O, Rivlin N, Molchadsky A, Madar S, Goldfinger N et al (2012) [cited 14 may 2020];56(3):656-662Available from https://doi.org/https://doi.org/10.1016/j.jhep.2011.08.022
Zaugg K, Yao Y, Reilly P, Kannan K, Kiarash R, Mason J et al (2011) Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev 25(10):1041–1051
Sanchez-Macedo N, Feng J, Faubert B, Chang N, Elia A, Rushing E et al (2013) [cited 14 may 2020];20(4):659-668Available from https://doi.org/https://doi.org/10.1038/cdd.2012.168
Assaily W, Rubinger D, Wheaton K, Lin Y, Ma W, Xuan W et al (2011) [cited 14 may 2020];44(3):491-501Available from https://doi.org/https://doi.org/10.1016/j.molcel.2011.08.038
Yahagi N, Shimano H, Matsuzaka T, Najima Y, Sekiya M, Nakagawa Y et al (2003) [cited 14 may 2020];278(28):25395-25400Available from https://doi.org/https://doi.org/10.1074/jbc.M302364200
Zhou G, Wang J, Zhao M, Xie T, Tanaka N, Sano D et al (2014) [cited 14 may 2020];54(6):960-974Available from https://doi.org/https://doi.org/10.1016/j.molcel.2014.04.024
Freed-Pastor W, Mizuno H, Zhao X, Langerød A, Moon S, Rodriguez-Barrueco R et al (2012) [cited 14 may 2020];148(1-2):244-258Available from https://doi.org/https://doi.org/10.1016/j.cell.2011.12.017
Jennis M, Kung C, Basu S, Budina-Kolomets A, Leu J, Khaku S et al (2016) [cited 14 may 2020];30(8):918-930Available from https://doi.org/https://doi.org/10.1101/gad.275891.115
Lowman X, Hanse E, Yang Y, Ishak Gabra M, Tran T, Li H et al P53 promotes cancer cell adaptation to glutamine deprivation by upregulating SLC7A3 to increase arginine uptake. Cell Reports [Internet]. 2019;26(11):3051-3060.e4. Available from https://doi.org/https://doi.org/10.1016/j.celrep.2019.02.037
Tajan M, Hock A, Blagih J, Robertson N, Labuschagne C, Kruiswijk F et al A role for P53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metabolism [Internet]. 2018 [cited 14 may 2020];28(5):721-736.e6. Available from https://doi.org/https://doi.org/10.1016/j.cmet.2018.07.005
Ou Y, Wang S, Jiang L, Zheng B, Gu W. P53 protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. Journal of Biological Chemistry [Internet]. (2014) [cited 14 may 2020];290(1):457-466Available from https://doi.org/https://doi.org/10.1074/jbc.M114.616359
Riscal R, Schrepfer E, Arena G, Cissé M, Bellvert F, Heuillet M et al (2016) [cited 14 may 2020];62(6):890-902Available from https://doi.org/https://doi.org/10.1016/j.molcel.2016.04.033
Kandoth C, McLellan M, Vandin F, Ye K, Niu B, Lu C et al (2013) [cited 20 July 2020];502(7471):333-339Available from https://doi.org/https://doi.org/10.1038/nature12634
Zhao D, Tahaney W, Mazumdar A, Savage M, Brown P. Molecularly targeted therapies for p53-mutant cancers. Cellular and Molecular Life Sciences [Internet]. (2017) [cited 26 July 2020];74(22):4171-4187Available from https://doi.org/https://doi.org/10.1007/s00018-017-2575-0
Foster B, Coffey H, Morin M, Rastinejad F (1999) Pharmacological rescue of mutant P53 conformation and function. Science. 286(5449):2507–2510
Madka V, Zhang Y, Li Q, Mohammed A, Sindhwani P, Lightfoot S et al (2013) [cited 20 July 2020];15(8):966-974 Available from https://doi.org/https://doi.org/10.1593/neo.13704
Zache N, Lambert J, Rökaeus N, Shen J, Hainaut P, Bergman J et al (2008) [cited 20 July 2020];2(1):70-80Available from https://doi.org/https://doi.org/10.1016/j.molonc.2008.02.004
Bykov V, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P et al (2002) [cited 20 July 2020];8(3):282-288Available from https://doi.org/https://doi.org/10.1038/nm0302-282
Lambert J, Gorzov P, Veprintsev D, Söderqvist M, Segerbäck D, Bergman J et al (2009) [cited 20 July 2020];15(5):376-388Available from https://doi.org/https://doi.org/10.1016/j.ccr.2009.03.003
Zhang Q, Bykov V, Wiman K, Zawacka-Pankau J. APR-246 reactivates mutant P53 by targeting cysteines 124 and 277. Cell Death & Disease [Internet]. (2018) [cited 20 July 2020];9(5)Available from https://doi.org/https://doi.org/10.1038/s41419-018-0463-7
Peng X, Zhang M, Conserva F, Hosny G, Selivanova G, Bykov V et al (2013) [cited 20 July 2020];4(10):e881-e881Available from https://doi.org/https://doi.org/10.1038/cddis.2013.417
Tessoulin B, Descamps G, Moreau P, Maïga S, Lodé L, Godon C et al (2014) [cited 20 July 2020];124(10):1626-1636Available from https://doi.org/10.1182/blood-2014-01-548800
Study of the safety and efficacy of APR-246 in combination with azacitidine - full-text wiew - ClinicalTrials.gov [Internet]. Clinicaltrials.gov. 2020 [cited 6 July 2020]. Available from: https://clinicaltrials.gov/ct2/show/NCT03588078
Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant myeloid neoplasms - full-text view - ClinicalTrials.gov [Internet]. Clinicaltrials.gov. 2020 [cited 6 July 2020]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03072043
Bykov V, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J et al (2005) [cited 20 July 2020];280(34):30384-30391Available from https://doi.org/https://doi.org/10.1074/jbc.M501664200
Zhao C, Grinkevich V, Nikulenkov F, Bao W, Selivanova G. Rescue of the apoptotic-inducing function of mutant P53 by small-molecule RITA. Cell Cycle [Internet]. (2010) [cited 21 July 2020];9(9):1847-1855Available from https://doi.org/https://doi.org/10.4161/cc.9.9.11545
Burmakin M, Shi Y, Hedstrom E, Kogner P, Selivanova G. Dual targeting of wild-type and mutant P53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vitro and in vitro. Clinical Cancer Research [Internet]. (2013) [cited 21 July 2020];19(18):5092-5103Available from https://doi.org/https://doi.org/10.1158/1078-0432.CCR-12-2211
Rivera M, Stinson S, Vistica D, Jorden J, Kenney S, Sausville E. Selective toxicity of the tricyclic thiophene NSC 652287 in renal carcinoma cell lines. Biochemical Pharmacology [Internet]. (1999) [cited 21 July 2020];57(11):1283-1295Available from https://doi.org/https://doi.org/10.1016/s0006-2952(99)00046-5
Nieves-Neira W, Rivera M, Kohlhagen G, Hursey M, Pourquier P, Sausville E et al DNA protein cross-links produced by NSC 652287, a novel thiophene derivative active against human renal cancer cells. Molecular pharmacology [Internet]. 1999;56(3):478-484. Available from https://doi.org/https://doi.org/10.1124/mol.56.3.478
Liu X, Wilcken R, Joerger A, Chuckowree I, Amin J, Spencer J et al (2013) [cited 21 July 2020];41(12):6034-6044Available from https://doi.org/https://doi.org/10.1093/nar/gkt305
Bauer M, Joerger A, Fersht A. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward P53-compromised cells. Proceedings of the National Academy of Sciences [Internet]. (2016) [cited 21 July 2020];113(36):E5271-E5280Available from https://doi.org/https://doi.org/10.1073/pnas.1610421113
Yu X, Vazquez A, Levine A, Carpizo D. Allele-specific P53 mutant reactivation. Cancer Cell [Internet]. 2012 [cited 21 July 2020];21(5):614-625. Available from: https://doi.org/https://doi.org/10.1016/j.ccr.2012.03.042
Salim K, Maleki Vareki S, Danter W, San-Marina S, Koropatnick J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vitro. Oncotarget [Internet]. 2016 [cited 21 July 2020];7(27):41363-41379. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.9133
Punganuru S, Madala H, Venugopal S, Samala R, Mikelis C, Srivenugopal K. Design and synthesis of a C7-aryl piperlongumine derivative with potent antimiCROTubule and mutant P53-reactivating properties. European Journal of Medicinal Chemistry [Internet]. 2016 [cited 21 July 2020];107:233-244. Available from: https://doi.org/https://doi.org/10.1016/j.ejmech.2015.10.052
Weinmann L, Wischhusen J, Demma M, Naumann U, Roth P, DasMahapatra B et al (2008) [cited 21 July 2020];15(4):718-729Available from https://doi.org/https://doi.org/10.1038/sj.cdd.4402301
Aggarwal M, Saxena R, Sinclair E, Fu Y, Jacobs A, Dyba M et al (2016) [cited 21 July 2020];23(10):1615-1627Available from https://doi.org/https://doi.org/10.1038/cdd.2016.48
Soragni A, Janzen D, Johnson L, Lindgren A, Thai-Quynh Nguyen A, Tiourin E et al (2016) [cited 21 July 2020];29(1):90-103Available from https://doi.org/https://doi.org/10.1016/j.ccell.2015.12.002
Zhang Y, Xu L, Chang Y, Li Y, Butler W, Jin E et al (2019) [cited 21 July 2020];23(1):160-171Available from https://doi.org/https://doi.org/10.1038/s41391-019-0172-z
Demma M, Maxwell E, Ramos R, Liang L, Li C, Hesk D et al (2010) [cited 21 July 2020];285(14):10198-10212Available from https://doi.org/https://doi.org/10.1074/jbc.M109.083469
Wassman C, Baronio R, Demir Ö, Wallentine B, Chen C, Hall L et al (2013) [cited 21 July 2020];4(1)Available from https://doi.org/https://doi.org/10.1038/ncomms2361
Hiraki M, Hwang S, Cao S, Ramadhar T, Byun S, Yoon K et al (2015) [cited 21 July 2020];22(9):1206-1216Available from https://doi.org/https://doi.org/10.1016/j.chembiol.2015.07.016
Boeckler F, Joerger A, Jaggi G, Rutherford T, Veprintsev D, Fersht A. Targeted rescue of a destabilized mutant of P53 by an in silico screened drug. Proceedings of the National Academy of Sciences [Internet]. (2008) [cited 21 July 2020];105(30):10360-10365Available from https://doi.org/https://doi.org/10.1073/pnas.0805326105
Kravchenko J, Ilyinskaya G, Komarov P, Agapova L, Kochetkov D, Strom E et al (2008) [cited 21 July 2020];105(17):6302-6307Available from https://doi.org/https://doi.org/10.1073/pnas.0802091105
Terzian T, Suh Y, Iwakuma T, Post S, Neumann M, Lang G et al (2008) [cited 21 July 2020];22(10):1337-1344Available from https://doi.org/https://doi.org/10.1101/gad.1662908
Li D, Marchenko N, Moll U. SAHA shows preferential cytotoxicity in mutant P53 cancer cells by destabilizing mutant P53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death & Differentiation [Internet]. (2011) [cited 21 July 2020];18(12):1904-1913Available from https://doi.org/https://doi.org/10.1038/cdd.2011.71
Li D, Marchenko N, Schulz R, Fischer V, Velasco-Hernandez T, Talos F et al (2011) [cited 21 July 2020];9(5):577-588Available from https://doi.org/https://doi.org/10.1158/1541-7786.MCR-10-0534
Vakifahmetoglu-Norberg H, Kim M, Xia H, Iwanicki M, Ofengeim D, Coloff J et al (2013) [cited 21 July 2020];27(15):1718-1730Available from https://doi.org/https://doi.org/10.1101/gad.220897.113
Vakifahmetoglu-Norberg H, Yuan J. A degradative detour for mutant TP53. Autophagy [Internet]. (2013) [cited 21 July 2020];9(12):2158-2160Available from https://doi.org/https://doi.org/10.4161/auto.26338
Padmanabhan A, Candelaria N, Wong K, Nikolai B, Lonard D, O’Malley B et al (2018) [cited 21 July 2020];9(1)Available from https://doi.org/https://doi.org/10.1038/s41467-018-03599-w
Parrales A, Ranjan A, Iyer S, Padhye S, Weir S, Roy A et al (2016) [cited 21 July 2020];18(11):1233-1243Available from https://doi.org/https://doi.org/10.1038/ncb3427
Wang J, Zhao Q, Qi Q, Gu H, Rong J, Mu R et al (2011) [cited 21 July 2020];112(2):509-519Available from https://doi.org/https://doi.org/10.1002/jcb.22941
Foggetti G, Ottaggio L, Russo D, Monti P, Degan P, Fronza G et al (2017) [cited 21 July 2020];1864(2):382-392Available from https://doi.org/https://doi.org/10.1016/j.bbamcr.2016.11.023
Gu H, Wang X, Rao S, Wang J, Zhao J, Ren F et al (2008) [cited 21 July 2020];7(10):3298-3305Available from https://doi.org/https://doi.org/10.1158/1535-7163.MCT-08-0212
Yi Y, Kang H, Kim H, Kong Y, Brown M, Bae I. Targeting mutant P53 by a SIRT1 activator YK-3-237 inhibits the proliferation of triple-negative breast cancer cells. Oncotarget [Internet]. 2013 [cited 21 July 2020];4(7):984-994. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.1070
Alexandrova E, Yallowitz A, Li D, Xu S, Schulz R, Proia D et al (2015) [cited 21 July 2020];523(7560):352-356Available from https://doi.org/https://doi.org/10.1038/nature14430
. Why therapeutic response may not prolong the life of a cancer patient: selection for oncogenic resistance. Cell Cycle [Internet]. (2005) [cited 21 July 2020];4(12):1693-1698Available from https://doi.org/https://doi.org/10.4161/cc.4.12.2259
Discovery MP, development of SAHA as an anticancer agent. Oncogene [Internet]. (2007) [cited 21 July 2020];26(9):1351-1356Available from https://doi.org/https://doi.org/10.1038/sj.onc.1210204
VanderMolen K, McCulloch W, Pearce C, Oberlies N. Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. The Journal of Antibiotics [Internet]. (2011) [cited 21 July 2020];64(8):525-531Available from https://doi.org/https://doi.org/10.1038/ja.2011.35
Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L et al (2011) [cited 21 July 2020];147(1):223-234Available from https://doi.org/https://doi.org/10.1016/j.cell.2011.08.037
Liao Y, Guo Z, Xia X, Liu Y, Huang C, Jiang L et al (2019) [cited 21 July 2020];38(1)Available from https://doi.org/https://doi.org/10.1186/s13046-019-1165-4
Wang L, Yu Y, Chow D, Yan F, Hsu C, Stossi F et al (2015) [cited 21 July 2020];28(2):240-252Available from https://doi.org/https://doi.org/10.1016/j.ccell.2015.07.005
Zhao K, Zhang S, Song X, Yao Y, Zhou Y, You Q et al. Gambogic acid suppresses cancer invasion and migration by inhibiting TGFβ1-induced epithelial-to-mesenchymal transition. Oncotarget [Internet]. 2017 [cited 21 July 2020];8(16):27120-27136. Available from: https://doi.org/https://doi.org/10.18632/oncotarget.15449
Xia G, Wang H, Song Z, Meng Q, Huang X, Huang X. Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2). Journal of Experimental & Clinical Cancer Research [Internet]. (2017) [cited 21 July 2020];36(1)Available from https://doi.org/https://doi.org/10.1186/s13046-017-0579-0
De la Monte SM, Sohn YK, Ganju N, Wands JR. P53-and CD95-associated apoptosis in neurodegenerative diseases. Laboratory investigation; a journal of technical methods and pathology. 1998 1;78(4):401-11. Available from: http://europepmc.org/abstract/MED/9564885
Gupta A, Shah K, Oza M, Behl T. Reactivation of P53 gene by MDM2 inhibitors: a novel therapy for cancer treatment. Biomedicine & Pharmacotherapy [Internet]. (2019) [cited 23 July 2020];109:484-492Available from https://doi.org/https://doi.org/10.1016/j.biopha.2018.10.155
Yee-Lin V, Pooi-Fong W, Soo-Beng A. Nutlin-3, a P53-Mdm2 antagonist for nasopharyngeal carcinoma treatment. Mini-Reviews in Medicinal Chemistry [Internet]. (2018) [cited 21 July 2020];18(2)Available from https://doi.org/https://doi.org/10.2174/1389557517666170717125821
Shangary S, Qin D, McEachern D, Liu M, Miller R, Qiu S et al (2008) [cited 21 July 2020];105(10):3933-3938Available from https://doi.org/https://doi.org/10.1073/pnas.0708917105
Zheng M, Yang J, Xu X, Sebolt JT, Wang S, Sun Y (2010) Efficacy of MDM2 inhibitor MI-219 against lung cancer cells alone or in combination with MDM2 knockdown, a XIAP inhibitor or etoposide. Anticancer Res 30(9):3321–3331
Mohammad R, Wu J, Azmi A, Aboukameel A, Sosin A, Wu S et al (2009) [cited 21 July 2020];8(1):115Available from https://doi.org/https://doi.org/10.1186/1476-4598-8-115
Lai Z, Yang T, Kim Y, Sielecki T, Diamond M, Strack P et al (2002) [cited 21 July 2020];99(23):14734-14739Available from https://doi.org/https://doi.org/10.1073/pnas.212428599
Davydov I, Woods D, Safiran Y, Oberoi P, Fearnhead H, Fang S et al (2004) [cited 21 July 2020];9(8):695-703Available from https://doi.org/https://doi.org/10.1177/1087057104267956
Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T et al (2009) [cited 22 July 2020];15(9):1082-1087Available from https://doi.org/https://doi.org/10.1038/nm.2014
Bonfigli A, Sirolla C, Testa R, Cucchi M, Spazzafumo L, Salvioli S et al (2012) [cited 22 July 2020];50(3):429-436Available from https://doi.org/https://doi.org/10.1007/s00592-012-0450-x
Kung C, Leu J, Basu S, Khaku S, Anokye-Danso F, Liu Q et al (2016) [cited 22 July 2020];14(10):2413-2425Available from https://doi.org/https://doi.org/10.1016/j.celrep.2016.02.037
Liu Z, Jin L, Yang J, Wang B, Wu K, Hallenborg P et al (2018) [cited 22 July 2020];67(11):2397-2409Available from https://doi.org/https://doi.org/10.2337/db18-0684
Peifer M, Fernández-Cuesta L, Sos M, George J, Seidel D, Kasper L et al (2012) [cited 22 July 2020];44(10):1104-1110Available from https://doi.org/https://doi.org/10.1038/ng.2396
Comprehensive molecular portraits of human breast tumours. Nature [Internet]. (2012) [cited 22 July 2020];490(7418):61-70Available from https://doi.org/https://doi.org/10.1038/nature11412
Integrated genomic analyses of ovarian carcinoma. Nature [Internet]. (2011) [cited 22 July 2020];474(7353):609-615Available from https://doi.org/https://doi.org/10.1038/nature10166
Song Y, Li L, Ou Y, Gao Z, Li E, Li X et al (2014) [cited 22 July 2020];509(7498):91-95Available from https://doi.org/https://doi.org/10.1038/nature13176
Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome?. Annals of internal medicine. 1969 1;71(4):747-52. Available from: https://doi.org/https://doi.org/10.7326/0003-4819-71-4-747
Ruijs M, Verhoef S, Rookus M, Pruntel R, van der Hout A, Hogervorst F et al (2010) [cited 22 July 2020];47(6):421-428Available from https://doi.org/https://doi.org/10.1136/jmg.2009.073429
McBride K, Ballinger M, Killick E, Kirk J, Tattersall M, Eeles R et al (2014) [cited 22 July 2020];11(5):260-271Available from https://doi.org/https://doi.org/10.1038/nrclinonc.2014.41
Cenini G, Sultana R, Memo M, Butterfield D. Elevated levels of pro-apoptotic P53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer’s disease. Journal of Cellular and Molecular Medicine [Internet]. (2008) [cited 22 July 2020];12(3):987-994Available from https://doi.org/https://doi.org/10.1111/j.1582-4934.2008.00163.x
Ohyagi Y, Asahara H, Chui D, Tsuruta Y, Sakae N, Miyoshi K et al (2004) [cited 22 July 2020];19(2):1-29Available from https://doi.org/https://doi.org/10.1096/fj.04-2637fje
Sajan F, Martiniuk F, Marcus D, Frey W, Hite R, Bordayo E et al (2007) [cited 22 July 2020];22(4):319-328Available from https://doi.org/https://doi.org/10.1177/1533317507302447
Mogi M, Kondo T, Mizuno Y, Nagatsu T. P53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain. Neuroscience Letters [Internet]. (2007) [cited 22 July 2020];414(1):94-97Available from https://doi.org/https://doi.org/10.1016/j.neulet.2006.12.003
Bae B, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y et al (2005) [cited 22 July 2020];47(1):29-41Available from https://doi.org/https://doi.org/10.1016/j.neuron.2005.06.005
Illuzzi J, Vickers C, Kmiec E. Modifications of P53 and the DNA damage response in cells expressing mutant form of the protein Huntingtin. Journal of Molecular Neuroscience [Internet]. (2011) [cited 22 July 2020];45(2):256-268Available from https://doi.org/https://doi.org/10.1007/s12031-011-9516-4
Ryan A, Zeitlin S, Scrable H. Genetic interaction between expanded murine Hdh alleles and P53 reveal deleterious effects of P53 on Huntington’s disease pathogenesis. Neurobiology of Disease [Internet]. (2006) [cited 22 July 2020];24(2):419-427Available from https://doi.org/https://doi.org/10.1016/j.nbd.2006.08.002
Kelly KJ, Plotkin Z, Vulgamott SL, Dagher PC. P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a P53 inhibitor. Journal of the American Society of Nephrology. 2003 1;14(1):128-38. Available from: https://doi.org/https://doi.org/10.1097/01.asn.0000040596.23073.01
Molitoris B, Dagher P, Sandoval R, Campos S, Ashush H, Fridman E et al (2009) [cited 22 July 2020];20(8):1754-1764Available from https://doi.org/https://doi.org/10.1681/ASN.2008111204
Zhang D, Liu Y, Wei Q, Huo Y, Liu K, Liu F et al (2014) [cited 22 July 2020];25(10):2278-2289Available from https://doi.org/https://doi.org/10.1681/ASN.2013080902
Lee Y, Bae S, Choi S, Ji J, Song G. Associations between the P53 codon 72 polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. Lupus [Internet]. (2012) [cited 22 July 2020];21(4):430-437Available from https://doi.org/https://doi.org/10.1177/0961203311434941
Macchioni P, Nicoli D, Casali B, Catanoso M, Farnetti E, Boiardi L, Salvarani C (2007) The codon 72 polymorphic variants of P53 in Italian rheumatoid arthritis patients. Clin Exp Rheumatol 25(3):416–421 Available from: http://europepmc.org/abstract/MED/9564885
Chen R, Chang C, Wang T, Huang W, Tsai C, Tsai F. P53codon 72 proline/arginine polymorphism and autoimmune thyroid diseases. Journal of Clinical Laboratory Analysis [Internet]. (2008) [cited 22 July 2020];22(5):321-326Available from https://doi.org/https://doi.org/10.1002/jcla.20249
We thank Dr. Y. Srinivasa Rao and Mr. Vinod Kumar Mugada for their continuous support and help to carry out the article review process.
Ethics approval and consent to participate
This is a review article; thus, it does not involve studies with human beings as participants performed by any of the authors.
Consent for publication
All authors provided the consent to publish the review article.
All the authors declared that there are no competing interests (none).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Feroz, W., Sheikh, A.M.A. Exploring the multiple roles of guardian of the genome: P53. Egypt J Med Hum Genet 21, 49 (2020). https://doi.org/10.1186/s43042-020-00089-x