Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ki-ras mutations are associated with an increased risk of relapse and death in colorectal cancer (CRC) patients, with some mutations being more aggressive than others. The present study examined the predictive value of different Ki-ras mutation types in a retrospective series of 430 Dukes' C stage CRC patients, of whom 208 (48%) had received adjuvant chemotherapy with 5-fluorouracil/levamisole or 5-fluorouracil/leucovorin. A total of 140 mutations were detected, the majority (58%, 81/140) being glycine to aspartate mutations in codons 12 and 13. Glycine to valine mutations in codon 12 (14%, 20/140) and other less frequent, non-specified mutation types (28%, 39/140) accounted for the remaining mutations. Kaplan-Meier survival analysis revealed that both Ki-ras wild-type and mutant patient groups derived significant survival benefit from chemotherapy. However, when patients were stratified according to the type of mutation, those with non-aspartate mutations appeared to gain more benefit from this treatment than those with aspartate mutations. Multivariate analysis that included other possible predictive factors in Dukes' C CRC (tumour site, patient sex, TP53 mutation) demonstrated that non-aspartate mutations in particular were associated with a significant survival benefit from chemotherapy (HR=0.11, 95% CI: 0.04-0.30, p<0.001). These results suggest that the type of Ki-ras mutation could be a clinically useful molecular marker for the identification of CRC subgroups that are likely to benefit from 5-fluorouracil-based adjuvant chemotherapy.
 ...
PMID:Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer. 1174 89

Many human cancers contain a hemizygous point missense mutation in p53, allowing expression of both wild-type and mutant p53. To understand the relationship between wild-type and mutant p53 in cells, we investigated the influence of a naturally occurring temperature-sensitive mutant p53 (valine to alanine substitution at codon 143: mp53-143ala) on the life span of normal human oral keratinocytes (NHOK) and the expression of wild-type p53. We also investigated the effect of the mutant p53 on the genetic stability of NHOK. The mp53-143ala extended the in vitro life span of NHOK by four-fold, but failed to overcome the M2 crisis stage for immortalization. The mp53-143ala notably suppressed wild-type p53 in NHOK at post-transcriptional levels. Moreover, the mp53-143ala notably increased both spontaneous and genotoxic agent-induced mutation frequency of a shuttle vector in NHOK. These data indicate that mutant p53 induces genetic instability by, in part, inhibiting the expression of wild-type p53 through a dominant negative role in cells expressing both mutant and wild-type p53.
 ...
PMID:The temperature sensitive mutant p53-143ala extends in vitro life span, promotes errors in DNA replication and impairs DNA repair in normal human oral keratinocytes. 1183 64

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.
 ...
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

Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkin's lymphoma characterized by cyclin D1 overexpression and the cytogenetic abnormality, the t(11;14)(q13;q32). MCL cell lines have been difficult to establish and in vitro studies of these neoplasms are scarce. We describe the establishment and characteristics of a new MCL cell line, Mino. The cells are large, growing singly and in small clumps in vitro. By flow cytometry, the immunophenotype was compatible with MCL (i.e. CD5+CD20+CD23-FMC7+). Conventional cytogenetics showed hyperdiploidy with multiple complex karyotypic abnormalities, but no evidence of the t(11;14), proven to be present only by fluorescence in situ hybridization and polymerase chain reaction (PCR) methods. Western blots showed expression of cyclin D1 but no detectable cyclin D2 and cyclin D3; the retinoblastoma protein was predominantly phosphorylated. There was expression of tumor suppressor gene products including p53, p16(INK4a), and p21(WAF1). Sequencing of the TP53 gene revealed a mutation (codon 147(valine-->glycine)) in exon 5. Epstein Barr virus was absent. In summary, Mino is a new MCL cell line that may be useful to study the pathogenesis of MCL.
 ...
PMID:Establishment and characterization of a new mantle cell lymphoma cell line, Mino. 1212 61

In vitro studies suggest that effective tumor suppression by p53 requires multiple domains to execute transcription-dependent and transcription-independent functions. We generated a mutant p53 allele in mice, p53(W25QL26S) (p53(QS)), containing an inactive transactivation domain to evaluate the importance of transactivation for p53-mediated tumor suppression. Recently, we discovered that the allele also contains a valine substitution for alanine at codon 135, which borders the DNA-binding domain. We found that p53(QSval135) bound to chromatin albeit less well than p53(QSala135), but both were equally deficient in transcriptional regulation, apoptosis induction in mouse embryo fibroblasts (MEFs), and suppression of tumor formation by E1A, Ha-Ras transformed MEFs. p53(QSval135) mice and p53-null mice exhibited identical tumor development kinetics and spectra in spontaneous and oncogene-initiated tumorigenicity assays, when tested in a homo- and heterozygous configuration. The p53(QSval135) allele did not have dominant negative functions and behaved as a null allele. Taken together, these data indicate that effective tumor suppression requires the transcriptional regulation function of p53, and they suggest that transactivation independent functions of p53 are unlikely to contribute significantly to tumor suppression in vivo.
 ...
PMID:p53 must be competent for transcriptional regulation to suppress tumor formation. 1575 Jun 33

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy.
 ...
PMID:Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. 1592 28

Development of new therapeutic agents for colon cancer is highly desirable. To this end, we screened a chemical library for new anticancer agents and identified a synthetic compound, 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT), which kills cancer cells more effectively than it kills normal human fibroblasts. The molecular mechanism of the antitumor action of DBPT was further analyzed in three human colorectal cancer cell lines. DBPT effectively inhibited the growth of colorectal cancer cells, independent of p53 and P-glycoprotein status, whereas normal fibroblasts were unaffected at the same IC50. Over time, DLD-1 cancer cells treated with DBPT underwent apoptosis. The general caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone partially blocked DBPT-induced apoptosis in a dose-dependent manner. DBPT-induced apoptosis, including cytochrome c release and caspase activation, was abrogated when c-Jun NH2-terminal kinase (JNK) activation was blocked with either a specific JNK inhibitor or a dominant-negative JNK1 gene. However, constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells, and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT-induced apoptosis. Our results suggested that DBPT induces apoptosis in colorectal cancer cell lines through caspase-dependent and caspase-independent pathways and that JNK activation was crucial for DBPT-induced apoptosis. DBPT and its analogues might be useful as anticancer agents.
 ...
PMID:Identification of a novel synthetic thiazolidin compound capable of inducing c-Jun NH2-terminal kinase-dependent apoptosis in human colon cancer cells. 1602 41

The p53 tumor suppressor is a tetrameric transcriptional enhancer, and its activity is compromised by mutations that cause amino acid substitutions in its tetramerization domain. Here we analyze the biochemical and biophysical properties of peptides corresponding to amino acids 319-358 of wild-type human p53, which includes the tetramerization domain, and that of a cancer-derived mutant with valine substituted for glycine 334. Unlike the wild-type peptide, the G334V peptide forms amyloid fibrils by a two-step process under physiological conditions of temperature and pH. Nevertheless, the G334V peptide is capable of forming heterooligomers with a wild-type peptide. Computational modeling of the G334V peptide structure suggests that substitution of valine for glycine 334 causes a local distortion that contributes to a beta-dominated structural transition leading to amyloid formation. Since the distortion is mostly on the surface, the mutant peptide is still able to form a pseudonative tetramer complex at higher concentrations and/or lower temperatures. Our study suggests a new potential mechanism by which mutations that compromise tetramer formation inactivate p53 as a tumor suppressor.
 ...
PMID:Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer. 1646 8

The E6 oncoproteins from high-risk mucosal human papillomavirus (HPV) induce cervical cancer via two major activities, the binding and the degradation of the p53 protein and PDZ domain-containing proteins. Human MAGI-1 is a multi-PDZ domain protein implicated into protein complex assembly at cell-cell contacts. High-risk mucosal HPV E6 proteins interact with the PDZ1 domain of MAGI-1 via a C-terminal consensus binding motif. Here, we developed a medium throughput protocol to accurately measure by surface plasmon resonance affinity constants of protein domains binding to peptidic sequences produced as recombinant fusions to the glutathione-S-transferase (GST). This approach was applied to measure the binding of MAGI-1 PDZ1 to the C-termini of viral or cellular proteins. Both high-risk mucosal HPV E6 C-terminal peptides and cellular partners of MAGI-1 PDZ1 bind to MAGI-1 PDZ1 with comparable dissociation constants in the micromolar range. MAGI-1 PDZ1 shows a preference for C-termini with a valine at position 0 and a negative charge at position -3, confirming previous studies performed with HPV18 E6. A detailed combined analysis via site-directed mutagenesis of the HPV16 C-terminal peptide and PDZ1 indicated that interactions mediated by charged residues upstream the PDZ-binding motif strongly contribute to binding selectivity of this interaction. In addition, our work highlighted the K(499) residue of MAGI-1 as a novel determinant of binding specificity. Finally, we showed that MAGI-1 PDZ1 also binds to the C-termini of LPP and Tax proteins, which were already known to bind to PDZ proteins but not to MAGI-1.
 ...
PMID:Surface plasmon resonance analysis of the binding of high-risk mucosal HPV E6 oncoproteins to the PDZ1 domain of the tight junction protein MAGI-1. 2084 23

This study examines the differential activities between wild-type Hepatitis B virus X protein (WtHBx) and a mutant HBx (MutHBx), which bears a hotspot mutation at nucleotides 1,762 and 1,764, resulting in a lysine to methionine change at codon 130 and a valine to isoleucine change at codon 131. This mutation leads to hepatocellular carcinoma, and we evaluated how WtHBx and MutHBx proteins differ in their interactions with the p53 tumor suppressor protein. This was experimentally addressed through co-immunoprecipitation assays examining the interaction between WtHBx and MutHBx proteins with p53, reporter assays determining the impact of the HBx proteins on p53-mediated gene transcription, and clonogenic survival assays evaluating the effect of HBx on cell growth in lines of varying p53-expression status. Both WtHBx and MutHBx proteins physically interact with p53 protein, but have different impacts on p53-mediated gene transcription. WtHBx did not effect p53-mediated gene transcription, whereas MutHBx inhibited it (P < 0.01). MutHBx inhibited colony formation in p53-proficient cells (P < 0.01), but not p53-deficient lines. Although both HBx proteins interact with p53, they affect p53-mediated gene transcription differently. WtHBx has no effect, whereas MutHBx inhibits it. In clonogenic survival assays, MutHBx inhibited cell growth in p53-proficient cells rather than enhanced it. This suggests that for MutHBx to behave oncogenically, the p53 pathway must be crippled or absent. This study has identified some important novel ways in which WtHBx and MutHBx differentially interact with p53 and this could begin to form the cellular explanation for the association between this particular mutant and liver cancer.
 ...
PMID:Interaction of mutant hepatitis B X protein with p53 tumor suppressor protein affects both transcription and cell survival. 2143 26


<< Previous 1 2 3 4 5 Next >>