Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin-centered chemotherapy is a key treatment for ovarian cancer, but resistance to chemotherapeutic agents remains a major cause of treatment failure. Multiple factors are known to contribute to the development of this chemoresistance. Although it has been demonstrated that X-linked inhibitor of apoptosis protein (Xiap) prevents apoptosis by inhibiting effector caspases, if and how it is important in chemoresistance in ovarian cancer has not been studied. The effects of Xiap down-regulation and/or restoration of wild type p53 by recombinant adenovirus infection were examined on four ovarian epithelial cancer cell lines [C13*, A2780-s (wild type p53), A2780-cp (mutant p53), and SKOV3 (null p53)]. Apoptosis and protein expression (e.g., Xiap, caspase-3, p53, MDM2, and p21waf1) were assessed by Hoechst 33258 stain and Western blot, respectively. We demonstrated that Xiap down-regulation following adenoviral antisense expression induces apoptosis in the wild-type p53 cells, but not in the mutated or null cells. Xiap down-regulation resulted in caspase-3 activation, caspase-mediated MDM2 processing, and p53 accumulation. Restoration of wild type p53 in the p53-mutated or -null cells significantly enhanced the proapoptotic effect of Xiap antisense expression. Down-regulation of Xiap induced apoptosis in chemoresistant ovarian cancer cells, a process dependent on p53 status.
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PMID:Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. 1105 57

MDM2 is a short-lived protein that regulates p53 degradation. We report here that transient coexpression of MDM2 and several p53 hotspot mutants resulted in stabilization and increased expression of MDM2. Ectopic expression of the mutant p53(175H) allele by recombinant adenovirus infection or stable transfection also stabilized endogenous MDM2 in p53-null cells. A panel of human tumor cell lines expressing different endogenous mutant p53 alleles also contained stabilized nuclear MDM2 at elevated levels when compared with p53-null cells. MDM2 was present in complexes with mutant p53 in tumor cells, and stabilization of MDM2 required direct binding to mutant p53. These results reveal a novel property of mutant p53 and a unique feature of tumors with p53 missense mutations. Accumulation of stable MDM2 may contribute to tumorigenesis through its p53-independent transforming functions.
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PMID:Stabilization of the MDM2 oncoprotein by mutant p53. 1115 66

Human MDM2 (hMDM2) inhibits transcriptional activation mediated by wild-type p53 and its tumor-derived mutants. We present evidence to show that hMDM2 interacts with the tumor-derived mutants of p53 and inhibits transcriptional activation of the human c-myc promoter mediated by the tumor-derived mutants of p53 through two domains. These two domains of hMDM2 are able to function independent of each other. Interaction with either of the domains is sufficient for inhibition of mutant p53-mediated transactivation. One of these domains is the same as the wild-type p53 interaction domain of hMDM2, whereas a second domain is situated within amino acid 190 and 276 residues and is specific for mutant p53. hMDM2 does not inhibit transcriptional activation mediated by the transcriptional activator VP16, suggesting that the inhibition is not mediated by inactivation of a general transcription factor. The transactivation and the oligomerization domains of mutant p53 are dispensable for its interaction with hMDM2. Thus, both hMDM2 and p53 recognize each other through unique domains. These observations suggest that forms of hMDM2 incapable of interacting with the wild-type p53, and are often expressed in transformed cells, would inhibit mutant p53-mediated transactivation and antagonize the tumorigenic function of mutant p53. This inhibitory function of hMDM2 may account for infrequent co-occurrence of p53 mutation and hMDM2 overexpression in cancer cells. Our results also suggest distinct mechanisms for wild-type and mutant p53-mediated transcriptional activation.
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PMID:The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants. 1117 71

The hallmark of Burkitt lymphoma (BL) is a constitutively activated c-myc gene that drives tumor cell growth. A majority of BL-derived cell lines also carry mutant p53. In addition, the p16INK4a promoter is hypermethylated in most BL biopsies and BL cell lines, leading to silencing of this gene. Activation of c-myc and/or cell cycle dysregulation can induce ARF expression and p53-dependent apoptosis. We therefore investigated the p14ARF-MDM2-p53 pathway in BL cell lines. p14ARF was expressed and localized to nucleoli in all BL carrying mutant p53. Three out of seven BL carrying wt p53 had a homozygous deletion of the CDKN2A locus that encodes both p14ARF and p16INK4a. Three BL carrying wild type p53 retained the CDKN2A locus and overexpressed MDM2. DNA sequencing revealed a point mutation in CDKN2A exon 2 in one of these BL, Seraphine. However, this point mutation did not affect p14ARF's nucleolar localization or ability to induce p53. The Bmi-1 protein that negatively regulates the p14ARF promoter and co-operates with c-myc in tumorigenesis was expressed at low to moderate levels in all BL analysed. Our results indicate that inactivation of the ARF-MDM2-p53 pathway is an essential step during the development of Burkitt lymphoma, presumably as a mechanism to escape c-myc induced apoptosis.
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PMID:p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53. 1136 Feb 1

Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.
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PMID:Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. 1150 71

Stabilization and overexpression are hallmarks of mutant p53 found in nearly 50% of human tumors. Mutations in the conformation-sensitive core domain of p53 often lead to association with molecular chaperones such as hsp70 and hsp90. Inhibition of hsp90 function accelerates mutant p53 degradation. We recently found that expression of p53 core domain mutants inhibits MDM2 degradation, suggesting that mutant p53 can modulate MDM2 functions. In this report, we show that mutant p53 mediates formation of MDM2-p53-hsp90 complexes. Release of MDM2 from the p53-hsp90 complex after DNA damage restores MDM2 but not p53 turnover, whereas dissociation of hsp90 by geldanamycin increases the degradation of both MDM2 and mutant p53. Mutant p53 degradation after hsp90 inhibition requires MDM2 expression. The interaction between MDM2 and hsp90 is disrupted by the 2A10 antibody, which recognizes a site on MDM2 important for binding to alternative reading frame (ARF). Expression of mutant p53 prevents MDM2 from binding ARF and accumulating in the nucleolus in an hsp90-dependent fashion. These results suggest that hsp90 recruited by mutant p53 conceals the ARF-binding site on MDM2 and inhibits its ubiquitin-protein isopeptide ligase function, resulting in the stabilization of both mutant p53 and MDM2.
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PMID:Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. 1150 88

The aminothiol WR1065, the active metabolite of the cytoprotector amifostine, exerts its antimutagenic effects through free-radical scavenging and other unknown mechanisms. In an earlier report, we showed that WR1065 activates wild-type p53 in MCF-7 cells, leading to p53-dependent arrest in the G(1) phase of the cell cycle. To determine whether WR1065 activates p53 by modulating protein conformation, we analyzed its effects on p53 conformation and activity in the esophageal cancer cell line TE-1. This cell line contains a mutation in codon 272 of p53 (p53(V272M), with methionine instead of a valine), conferring temperature-sensitive properties to the p53 protein. At the nonpermissive temperature (37 degrees C), p53(V272M) adopts the mutant p53 conformation (nonreactive with the antibody PAb1620), does not bind specifically to DNA, and is not activated in response to DNA-damaging treatment. However, treatment with 0.5-4 mM WR1065 partially restored wild-type conformation at 37 degrees C, stimulated DNA binding activity, and increased the expression of p53 target genes WAF-1, GADD45, and MDM2, leading to cell-cycle arrest in G(1). These results suggest that WR1065 activates p53 through a mechanism distinct from DNA-damage signaling, which involves modulation of p53 protein conformation.
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PMID:Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1. 1187 Aug 84

Antisense oligonucleotides have been investigated as anticancer agents administered alone or in combination with conventional chemotherapeutics. In the present study, we demonstrated synergistic effects between anti-MDM2 antisense oligonucleotides and the clinically used anticancer agent irinotecan, using nude mouse models of human colon cancers (LS174T and DLD-1). Surprisingly, a 5-base mismatch oligonucleotide also showed similar effects. To elucidate the underlying mechanisms, in vitro and in vivo pharmacokinetic and pharmacodynamic studies were performed. In LS174T cells, the antisense oligonucleotide, but not the mismatch oligonucleotide, specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p53 activation and p21 induction. In DLD-1 cells, the antisense oligonucleotide specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p21 induction although mutant p53 levels remained unchanged. Both oligonucleotides increased tissue uptake of irinotecan and the conversion of irinotecan to its active metabolite SN-38. These results suggest that oligonucleotides have a role in irinotecan metabolism and action, providing a basis for future development of antisense oligonucleotides as a sensitizer for irinotecan-based therapy.
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PMID:Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms. 1189 20

Although the N-terminal BOX-I domain of the tumor suppressor protein p53 contains the primary docking site for MDM2, previous studies demonstrated that RNA stabilizes the MDM2.p53 complex using a p53 mutant lacking the BOX-I motif. In vitro assays measuring the specific activity of MDM2 in the ligand-free and RNA-bound state identified a novel MDM2 interaction site in the core domain of p53. As defined using phage-peptide display, the RNA.MDM2 isoform exhibited a notable switch in peptide binding specificity, with enhanced affinity for novel peptide sequences in either p53 or small nuclear ribonucleoprotein-U (snRNP-U) and substantially reduced affinity for the primary p53 binding site in the BOX-I domain. The consensus binding site for the RNA.MDM2 complex within p53 is SGXLLGESXF, which links the S9-S10 beta-sheets flanking the BOX-IV and BOX-V motifs in the core domain and which is a site of reversible conformational flexibility in p53. Mutation of conserved amino acids in the linker at Ser(261) and Leu(264), which bridges the S9-S10 beta-sheets, stimulated p53 activity from reporter templates and increased MDM2-dependent ubiquitination of p53. Furthermore, mutation of the conserved Phe(270) within the S10 beta-sheet resulted in a mutant p53, which binds more stably to RNA.MDM2 complexes in vitro and which is strikingly hyper-ubiquitinated in vivo. Introducing an Ala(19) mutation into the p53(F270A) protein abolished both RNA.MDM2 complex binding and hyper-ubiquitination in vivo, thus indicating that p53(F270A) protein hyper-ubiquitination depends upon MDM2 binding to its primary site in the BOX-I domain. Together, these data identify a novel MDM2 binding interface within the S9-S10 beta-sheet region of p53 that plays a regulatory role in modulating the rate of MDM2-dependent ubiquitination of p53 in cells.
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PMID:The conformationally flexible S9-S10 linker region in the core domain of p53 contains a novel MDM2 binding site whose mutation increases ubiquitination of p53 in vivo. 1192 49

Human breast cancers, especially estrogen receptor alpha (ER(alpha))-positive ones, often overexpress the oncoprotein MDM2 without mdm2 gene amplification. The mdm2 gene is transcribed into two different mRNAs, namely L-mdm2 and S-mdm2, which are generated from promoters P1 (constitutive) and P2 (regulated by tumor suppressor p53), respectively. To cast light on the mechanisms of MDM2 overexpression, we measured the expression levels of these mdm2 mRNAs using RT-PCR analysis in three human breast cancer cell lines and 15 breast cancer samples obtained from surgery. ER(alpha)-positive MCF-7 cells, which possess wild-type p53, displayed dominant expression of S-mdm2. In contrast, two other cell lines with mutant p53, T47-D (ER(alpha)-positive) and MDA-MB-231 (ER(alpha)-negative), showed almost equivalent expression of L-mdm2 and S-mdm2. Treatment of 17beta-estradiol (E2) significantly enhanced the expression of S-mdm2 but not that of L-mdm2 in MCF-7. Among 6 breast cancer samples regarded as ER(alpha)-positive with wild-type p53, 5 samples showed increased expression of S-mdm2. Expression of S-mdm2 was stimulated in 2 ER(alpha)-positive samples with mutant p53. In contrast, 4 of 5 samples which express mutant p53 without ER(alpha) showed poor expression of S-mdm2. There is a tendency that ER(alpha)-positive breast cancers with wild-type p53 preferably use P2 promoter for the expression of mdm2, possibly through E2-induced accumulation of p53. However, wild-type p53 and ER(alpha) are not necessarily enough for the utilization of S-mdm2. Tumors with mutant p53 also showed expression of S-mdm2 in some cases. These results strongly suggest that other factor(s) is also implicated in the promoter usage of mdm2 gene in human breast cancer tissues.
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PMID:Distinct promoter usage of mdm2 gene in human breast cancer. 1195 27


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