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TP53  -  tumor protein p53

Homo sapiens

 
 
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Somatic disease relevance of TP53

  • Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas [1].
  • Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene [2].
  • The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo) [3].
  • Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway and TP53 inactivation (approximately 25% and 10% of cases, respectively) [4].
  • We found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/GADD153 (CHOP), SEL1L and SMURF1 [5].
  • These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression [6].
  • These results unravel a novel mechanism by which ERalpha opposes p53-mediated apoptosis in breast cancer cells [7].
  • Microarray data indicate that t(8;21) patient samples exhibit decreased expression of DNA repair genes and increased expression of p53 response genes compared with other acute myeloid leukemia (AML) patient samples [8].
  • In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma [9].
  • The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival [10].
  • These results show that a high proportion of neuroblastomas which relapse have an abnormality in the p53 pathway [11].

Germline disease relevance of TP53

  • Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene [12].
  • Four cancer types ("core cancers") are observed in families with germline TP53 mutations: All families had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC) [13].
  • Choroid plexus carcinoma and childhood adrenocortical carcinoma (ACC) are highly indicative of a germline TP53 mutation, regardless of family history [13].
  • Breast cancer is the most commonly observed tumor type among patients with germline TP53 mutations. In our cohort, all patients with breast cancer under the age of 30 and a family history of a core cancer had a germline TP53 mutation [13].
  • A combination of classic LFS criteria [14], Chompret criteria [15][16], and choroid plexus carcinoma regardless of family history yields a 99% sensitivity for detection of a germline TP53 mutation [13].
  • The frequency of de novo germline TP53 mutations is at least 7% and may be as high as 20% [17].
 

Psychiatry related information on TP53

 

High impact information on TP53

  • They show that the p38-regulated/activated protein kinase (PRAK) induces senescence downstream of oncogenic Ras by directly phosphorylating and activating the tumor-suppressor protein p53 [23].
  • Telomere dysfunction suppresses cancer through the p53 tumor suppressor pathway but also contributes to aging [24].
  • Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53 [25].
  • Furthermore, we show that PRAK activates p53 by direct phosphorylation [26].
  • In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA [27].
 

Chemical compound and disease context of TP53

 

Biological context of TP53

  • EP300 acetylation of TP53 in response to DNA damage regulates its DNA-binding and transcription functions [33].
  • Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression [34].
  • We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer [34].
  • Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa [34].
  • In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized [35].
 

Anatomical context of TP53

  • Thus, our results showed a relatively high frequency of TP53 mutations (76.8%) in our cell lines, with almost half of the mutations being truncating mutations [36].
  • Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease [37].
  • Hits identified by screening of a genome-scale siRNA library for cisplatin enhancers in TP53-deficient HeLa cells were significantly enriched for genes with annotated functions in DNA damage repair as well as poorly characterized genes likely having novel functions in this process [38].
  • Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes [39].
  • There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17) [40].
 

Associations of TP53 with chemical compounds

  • The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72 [41].
  • The in vitro cytotoxicity of a novel cyclin-dependent kinase inhibitor, CYC202, was evaluated in 26 B-CLLs, 11 with mutations in either the ATM or TP53 genes, and compared with that induced by ionizing radiation and fludarabine [42].
  • CYC202 induced apoptosis within 24 hours of treatment in all 26 analyzed tumor samples independently of ATM and TP53 gene status, whereas 6 of 26 B-CLLs, mostly ATM mutant, showed marked in vitro resistance to fludarabine-induced apoptosis [42].
  • Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively) [29].
  • We show that lysine methylation of p53 is important for its subsequent acetylation, resulting in stabilization of the p53 protein [43].
  • PRIMA-Dead, a compound structurally related to PRIMA-1 but unable to induce mutant p53-dependent apoptosis, failed to induce nucleolar translocation of mutant p53 [44].
  • Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability [45].
  • These data suggest that nutlin-3A stabilized p53 by preventing MDM2-mediated p53 degradation in HRS cells. wt p53 stabilization and activation by nutlin-3A may be a novel therapeutic approach for patients with HL [46].
  • Suppression of Rad51 expression, required for homologous recombination repair, blocked the ability of mutant p53 to antagonize arrest induced by etoposide, but not aphidicolin [47].
  • We show that monoubiquitination of p53, which causes it to localize to the cytoplasm and nucleoplasm, does not prevent the association of p53 with the nucleolus after MG132 treatment [48].
  • Triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5 [49].
  • In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody [50].
 

Physical interactions of TP53

  • Pull-down and co-immunoprecipitation assays demonstrated that p53 interacts specifically with securin both in vitro and in vivo [51].
  • Exposure to ionizing radiation of cells that stably express active or inactive c-Abl is associated with induction of c-Abl/p53 complexes and p21 expression [52].
  • These findings reveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also imply that HAUSP might function as a tumour suppressor in vivo through the stabilization of p53 [53].
  • The oncoprotein MDM2 binds to the activation domain of the tumor suppressor p53 and inhibits its ability to stimulate transcription [54].
  • Thus, in response to DNA damage, Chk2/hCds1 stabilizes the p53 tumor suppressor protein leading to cell cycle arrest in G(1) [55].
  • Bat3-depleted cells show reduced p53-p300 complex formation and decreased p53 acetylation [56].
  • We further demonstrate that BLIMP1 binds to the p53 promoter and represses p53 transcription, and this provides a mechanistic explanation for the induction of p53 response in cells depleted of BLIMP1 [57].
  • MDM2 binding to the p53 N terminus could induce a conformational change in wild-type p53 [58].
  • Deletion experiments indicate that the carboxyl-terminal region (amino acid residues 296-393) of p53 protein interacts with PAI-1 mRNA [59].
  • S100A2 bound monomeric p53 as well as tetrameric, whereas S100A1 only bound monomeric p53 [60].
  • ASPP2 primarily binds to the core domain of p53, whereas iASPP predominantly interacts with a linker region adjacent to the core domain [61].
 

Enzymatic interactions of TP53

  • Additional inducible amino- and carboxy-terminal sites in p53 are also phosphorylated by hCHK1, indicating that this is an unusually versatile protein kinase [62].
  • PPM1D also dephosphorylates p53 at phospho-Ser 15 [63].
  • PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner [64].
  • Both wild-type and tumor-derived mutant p53 proteins are efficiently phosphorylated by CAK [65].
  • p21waf1/cip1 mRNA and protein accumulate in intact cells exposed to oxidizing agents through a p53-independent, MAPK-dependent mechanism [66].
  • We show that Cdk5 phosphorylates p53 on Ser15, Ser33 and Ser46 in vitro, and that increased Cdk5 activity in the nucleus mediates these phosphorylation events in response to genotoxic and oxidative stresses [67].
 

Co-localisations of TP53

  • In cells arrested in S phase with hydroxyurea, WRN exits the nucleolus and colocalizes with p53 in the nucleoplasm [68].
  • Here, we report for the first time that during recovery from hydroxyurea treatment, the S100A2 protein translocated from the cytoplasm to the nucleus and co-localized with the tumor suppressor p53 in two different oral carcinoma cells (FADU and SCC-25) [69].
  • Interestingly, the MDM2 protein was found to co-localize with p53 to nucleolar structures following proteasome inhibition [70].
  • Large foci containing phosphorylated ATM and gamma-H2AX co-localized and foci with p53 phosphorylated at serine 15 also showed the same distribution [71].
  • Furthermore, nucleolin co-localized with p53 to these foci, suggesting that these foci were nucleolar structures [70].
 

Regulatory relationships of TP53

  • Conversely, YY1 overexpression stimulates p53 ubiquitination and degradation [72].
  • Securin also inhibits the ability of p53 to induce cell death [51].
  • We show that BTG2 expression is induced through a p53-dependent mechanism and that BTG2 function may be relevant to cell cycle control and cellular response to DNA damage [73].
  • Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53 [74].
  • The p53 tumour-suppressor protein controls the expression of a gene encoding the p21 cyclin-dependent protein kinase (CDK) regulator [75].
  • These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence [76].
  • Gene expression analysis showed that TRAILreceptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases [77].
  • We found the intracellular interaction between Notch1-IC and p53 in HCT116 p53(+/+) cells and suggest that activated Notch1 interaction with p53 is an important cellular event for the inhibition of p53-dependent transactivation [78].
  • Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53 [79].
  • PC4 activates p53 recruitment to p53-responsive promoters (Bax and p21) in vivo through its interaction with p53 and by providing bent substrate for p53 recruitment [80].
  • These findings indicate that DYRK2 regulates p53 to induce apoptosis in response to DNA damage [81].
  • Stabilization and activation of p53 are regulated independently by different phosphorylation events [82].
  • Disruption of acetyl-p53/bromodomain interaction inhibits TAF1 recruitment to both the distal p53-binding site and the core promoter [83].
  • This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation [84].
  • Consistent with these observations, exogenous expression of RAP80 selectively inhibits p53-dependent transactivation of target genes in an mdm2-dependent manner in MEF cells [85].
 

Other interactions of TP53

  • Upon activation of the ATR-intra-S phase checkpoint, Deltap53, but not p53, transactivates the Cdk inhibitor p21 [86].
  • Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways [87].
  • Mutations in TP53 and PTEN are mutually exclusive in either compartment [1].
  • p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest [88].
  • Yin Yang 1 is a negative regulator of p53 [72].
  • RNAi experiments demonstrate that CDK8 functions as a coactivator within the p53 transcriptional program [89].
  • These results support the hypothesis that Flt3-mediated signaling in AML enables accumulation of Bcl-2 and maintains a downstream block to p53 pathway apoptosis [90].
  • Together, we hypothesize that breast cancer patients with mutant p53 might benefit from targeted repression of BMP7 expression and/or targeted inhibition of the BMP7 pathway [91].
  • Further, depletion of SET8 augments the proapoptotic and checkpoint activation functions of p53, and accordingly, SET8 expression is downregulated upon DNA damage [92].
  • Both DR5 surface induction and synergy with Apo2L.0 are sensitive to siRNA-mediated downregulation of p53 [93].
  • We provide the first genetic evidence demonstrating that lysine methylation of p53 by Set7/9 is important for p53 activation in vivo and suggest a mechanistic link between methylation and acetylation of p53 through Tip60 [94].
  • We demonstrate that Lasp1 is indeed a bona fide p53 target by validating the functional repression effect of p53 on Lasp1 via a p53 response element [95].
 

Analytical, diagnostic and therapeutic context of TP53

 

References

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