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

p53-interacting proteins from mouse epidermal cells and human myelogenous leukemia cells were isolated by affinity chromatography using glutathione S-transferase (GST)-p53 fusion proteins. One of these proteins was topoisomerase I, whose interaction with p53 was recently reported. A carboxyl-terminal fragment containing the last 92 amino acids of p53 (GST-299-390) was sufficient for binding to topoisomerase I. Nanomolar concentrations of either GST-p53 or GST-299-390 enhanced the catalytic activity of purified human topoisomerase I. Purified wild-type human p53 and point mutants Ser-239, Ser-245, and His-273 were equivalent in their enhancement of human topoisomerase I activity. Because topoisomerase I is thought to promote genetic recombination, competence to enhance topoisomerase I catalytic activity coupled with a deficiency in transcriptional activity may be a mechanism for gain of function in mutant p53 proteins.
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PMID:Wild-type and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants. 960 49

We investigated the utility of examining biological markers to predict chemoresponse and survival. The subjects consisted of 39 unresectable gastric cancer patients treated with a combination of 5-fluorouracil and cis-platinum. The expression of p53, bcl-2, thymidylate synthase (TS), glutathione S-transferase pi (GST-pi), and vascular endothelial growth factor (VEGF) in the formalin-fixed biopsy samples of primary tumors before chemotherapy was examined immunohistochemically. The positive rate for VEGF, bcl-2, TS, p53, and GST-pi was 51, 10, 46, 38, and 69%, respectively. VEGF-positive cases showed a higher response rate than did negative cases (11 of 20 versus 2 of 19 cases; P = 0.0057). The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers. The 10 cases having 4 or 5 favorable phenotypes (VEGF positive, p53 negative, bcl-2 negative, TS negative, and GST-pi negative) survived longer than the remaining 29 cases (P = 0.0069). Multivariate analysis revealed that the number of favorable phenotypes (> or = 4 versus < or = 3) had a greater impact on survival than performance status (0 versus 1 or 2), age (> 60 years versus < or = 60 years), macroscopic type (scirrhous versus nonscirrhous), histological type (intestinal versus diffuse), or tumor extent (locally advanced versus metastatic). Immunohistochemical examination of biological markers in biopsy samples may be useful in predicting the clinical outcome of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.
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PMID:Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. 962 64

Choline deficiency (CD) was previously shown to trigger apoptosis in rat hepatocytes in culture and in vivo. In the present study we investigated the effects of short-term withdrawal of choline from the diet on the expression of putative preneoplastic foci in OXYS rats, an inbred strain with an inherited overproduction of free radicals. Animals were fed a defined, choline-sufficient (CS, control) or choline-deficient (CD) diet for 6 weeks. Eosinophilic, glutathione S-transferase (pi class) (+) preneoplastic foci were found in histologic sections of control OXYS rat liver. CD caused a 60% decrease in the number of eosinophilic foci per liver section (27.0+/-6.1 vs. 10.6+/-4.6 foci/section) compared to CS controls. Apoptotic bodies were detected in 0.18+/-0.03% of hepatocytes in CD livers compared to 0.05+/-0.009% of hepatocytes in controls. Cells which exhibited an apoptotic morphology in hematoxylin and eosin-stained sections were TUNEL-positive, confirming the induction of apoptosis. Also in CD animals compared to controls, there was an increased expression of p27Kip1 protein, and a reduction in PCNA nuclear labeling and the number of mitotic figures, consistent with an inhibition of cell proliferation in the livers of CD animals. This study shows that the liver of OXYS rats with an inherited overgeneration of free radicals retains sensitivity to CD, and that this p53-independent trigger of apoptosis can decrease the number of eosinophilic foci in the livers of these animals.
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PMID:Choline deficiency induces apoptosis and decreases the number of eosinophilic preneoplastic foci in the liver of OXYS rats. 964 30

The ankyrin 33-residue repeating motif, an L-shaped structure with protruding beta-hairpin tips, mediates specific macromolecular interactions with cytoskeletal, membrane, and regulatory proteins. The association between ankyrin and alpha-Na,K-ATPase, a ubiquitous membrane protein critical to vectorial transport of ions and nutrients, is required to assemble and stabilize Na,K-ATPase at the plasma membrane. alpha-Na,K-ATPase binds both red cell ankyrin (AnkR, a product of the ANK1 gene) and Madin-Darby canine kidney cell ankyrin (AnkG, a product of the ANK3 gene) utilizing residues 142-166 (SYYQEAKSSKIMESFK NMVPQQALV) in its second cytoplasmic domain. Fusion peptides of glutathione S-transferase incorporating these 25 amino acids bind specifically to purified ankyrin (Kd = 118 +/- 50 nM). The three-dimensional structure (2.6 A) of this minimal ankyrin-binding motif, crystallized as the fusion protein, reveals a 7-residue loop with one charged hydrophilic face capping a double beta-strand. Comparison with ankyrin-binding sequences in p53, CD44, neurofascin/L1, and the inositol 1,4,5-trisphosphate receptor suggests that the valency and specificity of ankyrin binding is achieved by the interaction of 5-7-residue surface loops with the beta-hairpin tips of multiple ankyrin repeat units.
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PMID:Structure of the ankyrin-binding domain of alpha-Na,K-ATPase. 966 35

Previous reports have documented an attenuated p53 response to DNA damage in hepatocytes isolated from enzyme-altered foci (EAF). Here, we have studied this p53 response in vivo in rats with EAF. These animals received repeated doses of diethylnitrosamine (DEN) for 6 weeks and a challenging dose 24 h before death. Liver sections were then analysed using an immunohistological procedure for p53, or a double-staining procedure for p53 and glutathione-S-transferase pi (GST-P). In control rats or rats with EAF not given the challenging dose of DEN, there was no p53 staining. In control rats, only given the challenging dose of DEN, there was a centrilobular p53 nuclear staining that co-localized with TUNEL staining. In an experiment involving four rats with EAF 389 +/- 39 hepatocytes/mm2 of non-EAF tissue stained positively for p53, while the corresponding value for EAF tissue was 27.6 +/- 7.5. Thus, p53-positive cells were 14.6-fold more frequent in non-EAF than in EAF tissue. In many EAF no p53-positive cells were seen at all and 83% of the EAF demonstrated <20% of the number of p53-positive cells seen in non-EAF tissue. Very few EAF had as high a proportion of p53-positive cells as did the average non-EAF tissue. EAF >0.06 mm2 had significantly fewer p53-positive cells than smaller EAF. The ratio of p53 expression in non-EAF tissue and large EAF was 32.6. In a control experiment, four EAF-bearing rats were used as donors to prepare primary cultures of hepatocytes. After 24 h of exposure to DEN, many of the cultured cells became p53-positive. Among GST-P-negative hepatocytes, 12.8% were p53-positive, whereas only 0.25% of the GST-P-positive hepatocytes were p53-positive. Literature data suggest that the altered xenobiotic metabolism in EAF may give rise to a 3-4-fold difference in DNA damage between non-EAF and EAF tissues. It is concluded that GST-P-positive EAF hepatocytes have an attenuated p53 response to DNA damage. This attenuated response may facilitate clonal expansion of EAF under stress induced by DNA-damaging chemicals.
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PMID:Wild-type p53 expression in liver tissue and in enzyme-altered foci: an in vivo investigation on diethylnitrosamine-treated rats. 968 82

SV40 T antigen downregulates the expression of an important detoxification enzyme, glutathione S-transferase alpha (GSTalpha). We show here that the target of this repression is a 14-bp element common to the human GSTA1 and GSTA2 promoters. This element, which we have named TAGR, is also critical for high-level, constitutive expression from these promoters. The TAGR element does not appear to contain a binding site for any transcription factor known to be present in fibroblasts, although the TAGR element does resemble the binding site for the Ikaros transcription factor found in hematopoietic cells. We also have identified a 47-amino-acid fragment of T antigen that includes amino acids 83-100 and 119-147, which is sufficient to repress transcription from the GSTalpha promoter in transient transcription assays. Thus, GSTalpha repression does not require binding of T antigen to pRb, p300, or p53, since the domains of T antigen required for binding these cellular proteins are missing from this T antigen fragment. We show, however, that this fragment does bind to three cellular proteins with approximate molecular weights of 54, 59, and 94 kDa.
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PMID:A 47-amino-acid fragment of SV40 T antigen represses transcription from human GSTalpha promoters. 979 Oct 19

Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.
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PMID:Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer. 979 76

Glutathione S-transferases are involved in the conjugation of a number of human carcinogens. The frequencies of the deletion alleles coding for GSTM1, and GSTT1, related to deficient conjugation of xenobiotics, as well as a recently reported variant in the exon 5 of GSTP1 were investigated in this study. A multiplex polymerase chain reaction based method for a rapid and high throughput genotype analysis of all three GSTM1, GSTT1 and GSTP1 genes in a single tube was developed. Leukocyte DNA from two hundred and thirty-nine (n = 239) breast cancer patients were genotyped. Tumors from a subset of these breast cancer patients (n = 131) have previously been investigated for mutations in the TP53 gene, levels of p53 protein accumulation and loss of heterozygosity at several loci on chromosome 17. When genetic alterations in the tumors were analyzed with respect to glutathione S-transferase genotypes, a significantly higher proportion of the patients with a G allele (GG + AG) of the GSTP1 had loss of heterozygosity at the TP53 gene locus mapping to 17p, compared with non-G allele carriers (74% versus 29%) (P = 0.018). The patients carrying the G allele of GSTP1 also had more frequently mutations in the TP53 gene in their tumor (38%), compared with patients with the AA genotype (21%) (P = 0.055). G allele carriers had predominantly deletion or transversion mutations in the TP53 gene (5 of 7 and 5 of 6 respectively). A higher frequency of the G allele carriers was observed among patients with negative lymph node status (P = 0.0004). A higher proportion of the patients with positive lymph node status at the time of diagnosis had a combined GSTM1 null/GSTT1 null genotype (P = 0.05). Patients who were homozygous for the deleted GSTM1 allele were found to have a significantly shorter overall survival (P = 0.036).
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PMID:Single tube multiplex polymerase chain reaction genotype analysis of GSTM1, GSTT1 and GSTP1: relation of genotypes to TP53 tumor status and clinicopathological variables in breast cancer patients. 982 36

The cDNA encoding the wild type p53 protein from flounder, Platichthys flesus, was expressed in Escherichia coli using the GST fusion protein system. Several milligrams of recombinant p53 protein were purified. This protein displayed an apparent molecular weight of 45,000 Da, a value which is very similar to Xenopus p53, but significantly greater than was expected based on the length of the open reading frame. Immunization of rabbits against purified p53 protein allowed the production of high titre polyclonal antiserum. This new polyclonal antibody recognized recombinant flounder p53 protein in Western blot. Cross reaction was also observed with recombinant Xenopus p53 protein but not with human p53 protein. Immunoblotting of the total protein extract from normal flounder ovaries did not reveal any p53 expression.
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PMID:Production of a polyclonal antibody raised against recombinant flounder p53 protein. 982 50

The predictive role in terms of pathological response and prognostic role of biomarkers such as GST-pi, p53, bcl-2 and bax expression, immuno-histochemically detected, and of the S-phase cell fraction, autoradiographically determined as thymidine labeling index (TLI), were investigated within a prospective randomized phase III clinical trial on squamous-cell carcinoma of the oral cavity, including surgery or primary chemotherapy (PCT), which foresaw the prospective determination of biological markers. Pathological response was defined as the achievement after PCT of a pathological complete remission or the presence of microresidual disease. The study was performed on tumors obtained from a series of 100 previously untreated patients with resectable T2-4N0-2M0 carcinoma. All biomarkers were unrelated, except for an inverse relation between TLI and GST-pi and a direct relation between bcl-2 and bax expression. In patients treated with surgery alone, 3-year disease-free survival (DFS) appeared to be weakly, but not significantly, related only to GST-pi and p53 expression. In patients treated with PCT, pathological response and DFS were independent of p53 expression and cell proliferation. Conversely, low GST-pi and bax expression were indicative of pathological response but lost relevance as predictors of DFS, whereas absence of bcl-2 was associated with high probability of 3-year DFS in the overall series as well as in non-responding patients. Within this latter sub-set, all patients with bcl-2-positive tumors relapsed within 1 year of surgery, whereas a 60% probability of 3-year DFS was observed for patients with bcl-2-negative tumors (p = 0.02). This interim analysis appears to indicate that some biofunctional markers can provide information on pathological response to PCT and could help in understanding treatment efficacy at a cellular level.
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PMID:Biological markers as indicators of pathological response to primary chemotherapy in oral-cavity cancers. 984 71


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