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].
• 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 [4].
• 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) [5].

Psychiatry related information on TP53

• TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption [6].
• In order to examine the role of the TP53 gene in the pathogenesis of schizophrenic disorders, we investigated the genetic association between a functional polymorphism rs1042522 and schizophrenia by sequencing the fragment covering 72Pro> Arg in 701 cases and 695 controls in this work [7].
• The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription [8].
• NF-kappaB/rel proteins, tumor suppressor p53, and oncogene c-Myc are critical transcription factors involved in coordinating cellular decision-making events in response to external stimuli [9].
• Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells [10].

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 [11].
• Telomere dysfunction suppresses cancer through the p53 tumor suppressor pathway but also contributes to aging [12].
• Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53 [13].
• Furthermore, we show that PRAK activates p53 by direct phosphorylation [14].
• 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 [15].

Chemical compound and disease context of TP53

• We determined the prognostic relevance of high-frequency MSI (MSI-H), TP53 mutations, and KRAS mutations in a well-defined group of patients with stage III colon cancer (N = 391), randomly assigned for adjuvant treatment with fluorouracil-based chemotherapy [16].
• In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy [17].
• Isogenic HCT116 and HCT116 TP53-/- colon cancer cells were exposed to the NO* donor Sper/NO, H2O2, hypoxia, or hydroxyurea, and their mRNA was analyzed using oligonucleotide microarrays [18].
• Methylation of CpG dinucleotides and/or CCWGG motifs at the promoter of TP53 correlates with decreased gene expression in a subset of acute lymphoblastic leukemia patients [19].
• Two paclitaxel(Ptx)-resistant ovarian cancer cell lines, 1A9/Ptx-10 and 1A9/Ptx-22, isolated from the 1A9 cell line (a clone of the A2780 line) by continuous exposure to Ptx and verapamil, have point mutations in their major beta-tubulin gene and in one or both alleles of their TP53 gene [20].

Biological context of TP53

• EP300 acetylation of TP53 in response to DNA damage regulates its DNA-binding and transcription functions [21].
• Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression [22].
• We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer [22].
• 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 [22].
• In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized [23].

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 [24].
• Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease [25].
• 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 [26].
• Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes [27].
• 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) [28].

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 [29].
• 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 [30].
• 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 [30].
• 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) [17].
• At the opposite, upon treatment with topoisomerase II inhibitors (doxorubicin or etoposide), the expression of TAp63 isoforms was clearly induced, independently of the TP53 status of cells [31].

Physical interactions of TP53

• Pull-down and co-immunoprecipitation assays demonstrated that p53 interacts specifically with securin both in vitro and in vivo [32].
• 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 [33].
• 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 [34].
• The oncoprotein MDM2 binds to the activation domain of the tumor suppressor p53 and inhibits its ability to stimulate transcription [35].
• Thus, in response to DNA damage, Chk2/hCds1 stabilizes the p53 tumor suppressor protein leading to cell cycle arrest in G(1) [36].

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 [37].
• PPM1D also dephosphorylates p53 at phospho-Ser 15 [38].
• PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner [39].
• Both wild-type and tumor-derived mutant p53 proteins are efficiently phosphorylated by CAK [40].
• p21waf1/cip1 mRNA and protein accumulate in intact cells exposed to oxidizing agents through a p53-independent, MAPK-dependent mechanism [41].

Co-localisations of TP53

• In cells arrested in S phase with hydroxyurea, WRN exits the nucleolus and colocalizes with p53 in the nucleoplasm [42].
• 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) [43].
• Interestingly, the MDM2 protein was found to co-localize with p53 to nucleolar structures following proteasome inhibition [44].
• Large foci containing phosphorylated ATM and gamma-H2AX co-localized and foci with p53 phosphorylated at serine 15 also showed the same distribution [45].
• Furthermore, nucleolin co-localized with p53 to these foci, suggesting that these foci were nucleolar structures [44].

Regulatory relationships of TP53

• Conversely, YY1 overexpression stimulates p53 ubiquitination and degradation [46].
• Securin also inhibits the ability of p53 to induce cell death [32].
• 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 [47].
• Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53 [48].
• The p53 tumour-suppressor protein controls the expression of a gene encoding the p21 cyclin-dependent protein kinase (CDK) regulator [49].

Other interactions of TP53

• Upon activation of the ATR-intra-S phase checkpoint, Deltap53, but not p53, transactivates the Cdk inhibitor p21 [50].
• Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways [51].
• 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 [52].
• Yin Yang 1 is a negative regulator of p53 [46].

Analytical, diagnostic and therapeutic context of TP53

• Point mutations within the TP53 gene were detected by use of polymerase chain reaction (PCR) in combination with constant denaturant gel electrophoresis [53].
• To determine the MDM2 and TP53 mRNA levels, Northern-blot analysis was performed [54].
• Identification of mutations in the tumor suppressor gene TP53 has implications for the molecular epidemiology and for the molecular pathology of human cancer [55].
• Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER [56].
• Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses [25].

References