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)

Human T-cell lymphotropic virus type I (HTLV-I) transforms T cells in vitro, and the viral transactivator Tax functionally impairs the tumor suppressor p53 protein, which is also stabilized in HTLV-I-infected T cells. Thus, the functional impairment of p53 is essential to maintain the viral-induced proliferation of CD4+ mature T cells. However, in the CD4+ leukemic cells of patients with adult T-cell leukemia/lymphoma (ATLL), the viral transactivator does not appear to be expressed, and p53 mutations have been found only in a fraction of patients. We sought to investigate whether p53 function is impaired, in ex vivo samples from patients with ATLL, in the absence of genetic mutations. Here we demonstrate that the p53 protein is stabilized also in ex vivo ATLL samples (10 of 10 studied) and that at least in 2 patients p53 stabilization was not associated with genetic mutation. Furthermore, the assessment of p53 function after ionizing radiation of ATLL cells indicated an abnormal induction of the p53-responsive genes GADD45 and p21(WAF1) in 7 of 7 patients. In 2 of 2 patients, p53 regulation of cell-cycle progression appeared to be impaired as well. Because p53 is part of a regulatory loop that also involves MDM2 and p14(ARF), the status of the latter proteins was also assessed in cultured or fresh ATLL cells. The p97 MDM2 protein was not detected by Western blot analysis in established HTLV-I-infected T-cell lines or ex vivo ATLL cell lysates. However, the MDM2 protein could be easily detected after treatment of cells with the specific proteasome inhibitor lactacystin, suggesting a normal regulation of the p53-MDM2 regulating loop. Similarly, p14(ARF) did not appear to be aberrantly expressed in ex vivo ATLL cells nor in any of the established HTLV-I-infected T-cell lines studied. Thus, p53 stabilization in HTLV-I infection occurs in the absence of genetic mutation and alteration of the physiologic degradation pathway of p53. (Blood. 2000;95:3939-3944)
 ...
PMID:p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells. 1084 31

In the present study we examined the localization and overexpression of heat shock proteins (hsps), mainly hsp90, in pancreatic carcinoma tissue compared with control tissue (including chronic pancreatitis and normal pancreas tissue), with the aid of immunohistochemical staining, in situ hybridization and reverse transcriptase polymerase chain reaction. Hsp90 alpha mRNA was overexpressed more highly in pancreatic carcinoma than in the control tissue. The proliferating-cell-nuclear-antigen labeling index was also high in pancreatic carcinoma tissue compared with the other tissue. These findings suggest that the overexpression of hsp90 alpha mRNA in carcinomas may be correlated with cell proliferation. However, hsp90 beta was constitutively overexpressed almost equally in all groups of pancreatic tissue including pancreatic carcinoma, chronic pancreatitis and normal pancreas tissue. Immunohistochemical staining demonstrated a differentiation in the expression of hsp90 between histological types of pancreatic carcinoma. These findings suggest that hsp90 alpha is involved in carcinogenesis and that hsp90 beta is correlated to structural conformation. Hsp90 alpha and hsp90 beta seem to perform different functions in tissue containing malignant cells. P53, MDM2 and WAF1, that were cell-cycle-related oncogene product were more strongly expressed in the nuclei of the cancer cells of the cancer tissue. Especially, MDM2 was more strongly expressed in mucinous carcinoma and the mucin secreting tissues surrounding pancreatic carcinoma tissue. The expression of MDM2 protein might also be correlated to secretion systems during structural conformation and be correlated to hsp90 beta.
 ...
PMID:Overexpression and localization of heat shock proteins mRNA in pancreatic carcinoma. 1085 51

MDM2 is one of the downstream target genes for transcriptional activation by the product of the p53 tumor-suppressor gene. Transactivation of MDM2 gene expression is represented by the presence of a functional p53 protein. We hypothesized that MDM2 mRNA expression may be a more suitable prognostic factor than p53 or MDM2 protein expression and p53 gene mutations. In this study, expression of MDM2 mRNA, p53 protein, and MDM2 protein and mutations of the p53 gene were assessed in 81 lung tumor tissue specimens using RT-PCR, immunohistochemistry, and direct sequencing among exons 5-8, respectively. By immunohistochemistry, 33 and 42 of 81 patients with p53 (40.7%) and MDM2 (51.5%) protein expression were found in lung tumor specimens, respectively. The p53 direct sequencing data indicated that 13 of 81 patients (16.0%) had p53 mutations. However, Kaplan-Meier analysis showed that p53 protein and MDM2 protein expression and p53 mutation were not useful as prognostic factors. Interestingly, the survival of patients with MDM2 mRNA expression was longer than that of patients without MDM2 mRNA expression, though MDM2 mRNA expression was not associated with clinicopathological parameters, including tumor grade, tumor stage, tumor type, and TNM values. Moreover, Cox regression analysis showed that MDM2 mRNA expression was a significantly independent favorable prognostic factor in non-small-cell lung cancer (NSCLC) patients. Thus, measuring MDM2 mRNA expression using RT-PCR may be a simple, useful approach for predicting the survival of NSCLC patients.
 ...
PMID:MDM2 mRNA expression is a favorable prognostic factor in non-small-cell lung cancer. 1086 3

MDM2 is a p53-responsive molecule that when overexpressed, can alter growth control pathways via p53-dependent and independent mechanisms. We have identified a mutant p53 containing line that expresses high levels of transcripts that are regulated by the p53-responsive promoter of the MDM2 gene. Analysis of cloned product obtained from these tumor cells revealed that they harbor a mutant p53 protein (possessing an Arg to Gln substitution at codon 213) that is a potent transactivator of MDM2 expression. Consistent with this activity, the R213Q mutant was found to have the ability to interact with DNA sequences located within the MDM2 promoter. In contrast to previously described tumor-derived p53 mutants which retain MDM2 transactivation function and possess partial growth suppressive activity, the R213Q mutant is severely compromised in its ability to induce p53-regulated transcripts that encode for proteins involved in cell-cycle arrest and apoptosis. The R213Q mutant can also be expressed at high levels in stably transfected cells and cells that harbor this mutant possess elevated levels of MDM2 protein. The R213Q mutant was also found to be able to up-regulate MDM2 during a genotoxic stress response. R213Q is the first described tumor-derived p53 mutant that is deficient at up-regulating both cell cycle arrest and apoptotic factors, but is highly proficient at inducing the growth-promoting molecule MDM2.
 ...
PMID:Identification of a tumor-derived p53 mutant with novel transactivating selectivity. 1087 62

The MDM2 protein, through its interaction with p53, plays an important role in the regulation of the G(1) checkpoint of the cell cycle. In addition to binding to and inhibiting the transcriptional activation function of the p53 protein, MDM2 binds, inter alia, to RB and the E2F-1.DP-1 complex and in so doing may promote progression of cells into S phase. Mice transgenic for Mdm2 possess cells that have cell cycle regulation defects and develop an altered tumor profile independent of their p53 status. MDM2 also blocks the growth inhibitory effects of transforming growth factor-beta1 in a p53-independent manner. We show here that a novel growth regulatory molecule is also the target of MDM2-mediated inhibition. Using a yeast two-hybrid screen, we have identified a gene that encodes a novel cellular protein (MTBP) that binds to MDM2. MTBP can induce G(1) arrest, which in turn can be blocked by MDM2. Our results suggest the existence of another growth control pathway that may be regulated, at least in part, by MDM2.
 ...
PMID:A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. 1090 33

Transcriptional factor E2F-1 as well as tumor suppressor p53 have been shown to cause apoptosis independently in some types of human cancer cells when overexpressed. Here we report that sequential transfer of the wild-type p53 and E2F-1 genes efficiently induces apoptosis in human esophageal cancer cells and that E2F-1 overexpression directly, activates expression of p14 (ARF), which inhibits MDM2-mediated p53 degradation, resulting in the stabilization of p53. Infection of human esophageal cancer cell lines T.Tn and TE8 with adenovirus vector-expressing E2F-1 (Ad-E2F-1) enhanced mRNA and protein expression of ARF and decreased MDM2 protein expression. Transfection of ARF plasmid decreased MDM2 protein expression, which in turn increased p53 protein expression. Infection of T.Tn and TE8 cells first with adenovirus-expressing wild-type p53 (Ad-p53) and then with Ad-E2F-1 resulted in rapid induction of apoptosis; in contrast, simultaneous infection with Ad-E2F-1 and Ad-p53 had no significant antitumor effect. As shown by Western blot analysis, infection with suboptimal concentrations of Ad-E2F-1 induced the accumulation of exogenous p53 transduced by suboptimal concentrations of Ad-p53. Moreover, Ad-E2F-1-mediated ARF expression inhibited the up-regulation of MDM2 by overexpressed p53 in TE8 cells. Thus, overexpression of ectopic E2F-1 protein may stabilize endogenous as well as ectopic p53 protein via the E2F-1/ARF/MDM2/p53 regulatory pathway and, in this way, render cells more sensitive to apoptosis, an outcome that has important implications for the treatment of human esophageal cancers.
 ...
PMID:Induction of apoptosis in human esophageal cancer cells by sequential transfer of the wild-type p53 and E2F-1 genes: involvement of p53 accumulation via ARF-mediated MDM2 down-regulation. 1091 34

Aberration of the p53 gene is thought to be the most frequent genetic alteration in human cancers. Tp53 protein may be inactivated by the binding of the MDM2 protein. MDM2, the product of the mdm2 gene, is an oncoprotein that binds to Tp53 and inhibits the p53-mediated transactivation. MDM2 overexpression has been reported in several human cancers, but not in intrahepatic cholangiocarcinoma (ICC). Therefore, we have evaluated the immunohistochemical overexpression of MDM2 and the relationship between its expression and histological grade, clinicopathological features, Tp53 overexpression, and Ki-67 labeling index in 47 cases of ICC. MDM2 and Tp53 were found to be overexpressed in 38% and 57% of the tumor, respectively. MDM2 and Tp53 were not expressed in non-tumorous liver tissue. There was no significant difference between the MDM2 overexpression and ICC tumor grade. However, MDM2 overexpression correlated with the presence of metastases (P<0.01) and advanced tumor stage (P<0.05). MDM2 overexpression also correlated with Tp53 overexpression (P<0.03) and Ki-67 labeling index (P<0.03). Our findings suggest that MDM2 overexpression may play a role in the late stage of human ICC.
 ...
PMID:Overexpression of MDM2 protein in intrahepatic cholangiocarcinoma: relationship with p53 overexpression, Ki-67 labeling, and clinicopathological features. 1096 76

P53 plays a critical role in G1 checkpoint after DNA damage. MDM2 gene is a p53 target gene and its protein forms a feedback loop with p53 and inhibits p53-mediated G1 arrest. Sterigmatocystin (ST) is a mycotoxin and carcinogen. In this study we show that exposure of cells to ST for 12 or 24 h resulted in failure of G1 arrest at both time points. Accordingly, p53 protein was not increased and p21WAF1 expression was inhibited at 12 h, and both proteins were weakly induced at 24 h after treatment with ST. Meanwhile, MDM2 protein was induced in a p53-dependent fashion by ST at both 12 and 24 h. The induction of MDM2 was coincident with the cellular responses of p53 and p21WAF1, and might contribute to the failure of G1 arrest in ST-treated cells. In addition, ST-treated cells exhibited G2M arrest, regardless of p53 status. Our results indicate that the carcinogenic effects of ST seem to be mediated by failure of p53-mediated G1 checkpoint.
 ...
PMID:Absence of p53-mediated G1 arrest with induction of MDM2 in sterigmatocystin-treated cells. 1099 85

Forty-nine cases of synovial sarcoma were evaluated for mutation of the p53 gene, amplification of the MDM2 gene and mutation of the H-ras gene, and for the relation of these factors to overall survival and clinicopathologic parameters. All investigations were carried out on formalin-fixed paraffin-embedded materials. Furthermore, we evaluated the expression of p53 protein, MDM2, and p21(WAF1/CIP1) immunohistochemically in these cases, together with an assessment of proliferative activities using monoclonal antibody MIB-1. Nine of the 49 cases (18.4%) had p53 gene alteration detected by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. Eleven cases (24%) showed nuclear accumulation of p53 protein in more than 10% of the tumor cells. Among them, only three cases contained gene mutations. There was no correlation between p53 nuclear accumulation and p53 gene alteration. MDM2 gene amplification, as shown by differential PCR, was observed in 19 out of 47 cases (40%). Nineteen out of 49 cases (38.8%) showed immunoreactivity for MDM2. MDM2 gene amplification and the expression of MDM2 protein showed a significant positive relationship (P = 0.0004). Moreover, MDM2 immunoreaction was significantly correlated with nuclear accumulation of p53 protein (P = 0.023). Positive immunoreaction for p21(WAF1/CIP1) was observed in 21 out of 48 cases (43.8%). p21(WAF1/CIP1) expression was correlated with p53 protein expression. H-ras gene mutations were seen in only three cases (6.1%). All mutations were in codon 12 (one GGC-to-AGC [Gly-to-Ser] mutation and two GGC-to-GAC [Gly-to-Ap] mutations). The gene alteration of p53, MDM2, and H-ras did not affect the patients' prognosis. Although the cases with positive immunoreaction for p53 tended to have a worse prognosis, the difference was not statistically significant (P = 0.13). No correlation was observed between MIB-1 LI and the immunohistochemical expression of p53, MDM2, and p21(WAF1/CIP1) or the mutation status of p53 and H-ras. On the other hand, high MIB-1 LI (more than 10) significantly correlated with poor prognosis (P < 0.0001). Our results suggest that p53 gene mutation does not appear to be a major prognostic factor and H-ras mutations are infrequent in synovial sarcoma.
 ...
PMID:Molecular abnormalities of p53, MDM2, and H-ras in synovial sarcoma. 1100 40

We examined p53 protein stability and DNA damage-induced p53-dependent responses in a human leukemic CEM cell line and two teniposide-resistant sublines, CEM/VM-1 and CEM/VM-1-5 ( approximately 40 and 400-fold resistant to teniposide, respectively). Although all cell lines contain the same p53 mutations at codons 175 (Arg-->His) and 248 (Arg-->Gln), the constitutive levels of p53 were progressively increased with the resistance of the cells to teniposide. By pulse-chase experiments, we found that the half-lives of mutant p53 protein were approximately 12, 17, and >30 h in CEM, CEM/VM-1, and CEM/VM-1-5 cells, respectively. The prolonged half-lives of p53 in these cells is consistent with the fact that the protein harbors the indicated mutations. Of note, however, is the fact that the increased p53 protein half-lives in the two drug-resistant cell lines corresponds to a proportional decrease in MDM2 protein levels but an increase in p53-MDM2 binding interactions. This suggests that MDM2-mediated p53 degradation may be altered in our leukemic cell lines. The DNA damage-induced p53 response is fully functional in the drug-sensitive CEM cells containing a mutant p53, but this pathway is attenuated in the drug-resistant cells. Specifically, while the mutant p53 was phosphorylated at serine-15 in response to ionizing radiation in all these cell lines, mutant p53 induction in response to teniposide or ionizing radiation and induction of the p53-target genes, p21 and GADD45 only occurred in the drug-sensitive CEM cells. As assessed by MTT cytotoxicity assay, CEM cells were also significantly more sensitive to ionizing radiation, compared to the drug-resistant cell lines, and this correlated with p53 induction. Collectively, these results suggest that changes in constitutive mutant p53 protein levels, p53-MDM2 binding interactions, and altered regulation of the DNA damage-inducible p53-dependent pathway may play a role in drug- and radiation-responsiveness in these cells.
 ...
PMID:Differences in mutant p53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM cells. 1104 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>