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)

The diet contains various mutagens and carcinogens that can be classified into three groups: naturally occurring chemicals, synthetic compounds and compounds produced by cooking. The first group includes mycotoxins and plant alkaloids while the second is exemplified by food additives and pesticides. The third includes polycyclic aromatic hydrocarbons and heterocyclic amines (HCAs). HCAs are mutagenic to microbes and eukaryotes and their precursors are creatine or creatinine, sugars, and amino acids in meat and fish. Among 10 HCAs so far examined for carcinogenicity in rodents, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced colon cancer in rats. PhIP is an especially interesting compound inducing colon tumors specifically in male F344 rats and only very rarely in females, which develop mammary carcinomas at high frequency instead. Since induced DNA adduct levels, determined by the 32P-postlabeling method, were found to be almost the same in male and female F344 rats adduct formation in itself is not directly responsible for carcinogenesis. We established, however, that PhIP causes increased cell proliferation in colon mucosa but not in the non-target liver or kidney of male rats. Induction of cell proliferation is therefore possibly an additional important factor determining carcinogenic organ specificity. In terms of molecular alteration ras family gene mutations are very rare and no mutations are evident in the p53 gene in colon tumors induced by HCAs. Their development due to HCAs can thus be considered an appropriate experimental model for human colon tumors in which ras or p53 gene activation is not involved. Since HCAs are genotoxic compounds, a causal role in some stage of human colon carcinogenesis is plausible. Exposure to HCAs should accordingly be avoided as far as possible.
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PMID:Carcinogenic factors in food with relevance to colon cancer development. 769 98

In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.
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PMID:Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene. 1019 Jul 88

Expression of the lung resistance protein (LRP) is associated with resistance to various anticancer drugs including melphalan and, therefore, may affect the clinical outcome in multiple myeloma (MM). To determine the clinical significance of LRP, we have compared LRP expression in bone marrow plasma cells with clinical parameters including response to chemotherapy and survival of previously untreated patients with MM (n = 72). LRP expression immunocytochemically assessed by means of the LRP-56 monoclonal antibody was positive (> or =10% staining plasma cells) in 44 (61%) samples. There was no correlation between LRP expression and age, sex, type of the paraprotein, serum creatinine, stage, beta2-microglobulin, serum lactate dehydrogenase, or C-reactive protein. However, LRP expression was more frequently observed in patients with a p53 deletion than in those without such a deletion (P = 0.01). The overall response rate for all of the patients evaluable for response to induction chemotherapy (n = 58) was 67%. The response rate was 87% for patients without LRP expression but only 54% for patients with LRP expression (P = 0.01). Kaplan-Meier analysis revealed that patients with LRP expression had a shorter overall survival (median, 33 months) than those without LRP expression (median not reached; P = 0.04). These data show that LRP expression is an important marker for clinical drug resistance and predicts a poor outcome in MM.
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PMID:Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. 1049 14

The goal of this study was to clarify the role of p21, a cyclin-dependent kinase inhibitor, in acute renal failure (ARF). This was accomplished with the examination of the renal expression of p21 in cisplatin (CDDP)-induced ARF and in rechallenge injury with CDDP. The injection of CDDP (5 mg/kg) into rats induced increases in serum creatinine and tubular damage and the number of in situ DNA nick end labeling-positive cells, which peaked at day 5, followed by recovery to control levels by day 14. The rechallenge with the same dose of CDDP 14 d after the first dose of CDDP induced significantly less injury and no significant increase in in situ DNA nick end labeling-positive cells. The first CDDP dose significantly increased p53-positive nuclei at day 1, which disappeared by day 5, and the number of p21-positive nuclei, which had two peaks on days 3 and 9. The number of proliferating cell nuclear antigen (PCNA)-positive nuclei peaked at days 3 and 12. A significant increase in the incorporation of 5-bromo 2'-deoxyuridine (BrdU) was found at day 5 and peaked at day 7. The second injection of CDDP induced significant increases in the number of p21-, p53-, and PCNA-positive nuclei within 2 d but did not affect the incorporation of BRDU: These findings suggested that (1) CDDP induced two peaks of the increase in p21; (2) the first peak occurred shortly after CDDP and was accompanied by overexpression of p53 and PCNA but not with BrdU incorporation, possibly reflecting G1 arrest and DNA repair; (3) the second peak of p21 occurred through an p53-independent pathway and may contribute to cell differentiation; and (4) the overexpression of p21 and PCNA in rechallenge injury may contribute to acquired resistance in CDDP-induced ARF via enhanced DNA repair.
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PMID:Role of the increase in p21 in cisplatin-induced acute renal failure in rats. 1131 48

Albuminuria is a widely recognized marker of renal disease and cardiovascular risk. This is especially true in Aboriginal Australians living in remote communities who suffer high rates of end-stage renal disease and cardiovascular mortality. During a survey of risk factors for renal and cardiovascular disease in one such community, an association between a common polymorphism at codon 72 (Arg/Pro) of the p53 gene and markers of renal disease was sought. A cross-sectional community survey including 217 people was performed. Genotypes of the polymorphism were distributed in Hardy-Weinberg equilibrium, with p53Arg allele frequency of 0.45 (range, 0.41 to 0.50). Overall prevalence of albuminuria was high (31% microalbuminuria; 14% overt albuminuria). Urine albumin/creatinine ratio (ACR) was significantly associated with the number of p53Pro alleles (P = 0.01), and there was an interaction with tobacco smoking (P = 0.04). The p53 genotype was also associated with increasing HbA1c, but the relationship between p53 and ACR was independent of this. This is a previously unreported association. This study does not address the mechanism, but this finding, if confirmed, expands the described effects of p53 in cellular proliferation and apoptosis to include a role in the course of renal and possibly cardiovascular disease in this population.
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PMID:The p53Pro72Arg polymorphism is associated with albuminuria among aboriginal Australians. 1185 71

Conflicting data are reported on the clinical significance of cyclin D1 deregulation in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of cyclin D1 expression and p53 mutations in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of cyclin D1 and p53 was analyzed using standard immunohistochemical method of B5-fixed and routinely processed paraffin-embedded bone marrow specimens. Cyclin D1 was overexpressed in 14/59 (27%) and p53 in 5/59 (8.5%) specimens. There was no significant correlation between cyclin D1 overexpression and age, gender, clinical stage (Durie-Salmon classification), extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, C-reactive protein, and beta2-microglobulin. No association was observed between the expression of cyclin D1 and the extent of bone marrow infiltration, histological grade, proliferative activity index (measured with Ki-67 immunoreactivity) and response to therapy. No significant difference was observed regarding overall survival between cyclin D1 positive and cyclin D1 negative patients (29 vs 36 mo, p = 0.76). Results of this study did not revealed prognostic significance of cyclin D1 overexpression in multiple myeloma. Mutations of p53 gene are rare events in myeloma, suggesting their limited role in the pathogenesis of the disease.
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PMID:Immunohistochemical analysis of cyclin D1 and p53 in multiple myeloma: relationship to proliferative activity and prognostic significance. 1503 17

Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure.
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PMID:Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. 1517 83

Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 +/- 54.1 pmol/min/mg versus 160.7 +/- 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 +/- 5.9 nuclei or 9.4 +/- 0.6 cells per high-power field [HPF] versus 6.3 +/- 2.2 nuclei or 4.4 +/- 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 +/- 1.4 cells/HPF versus 0.8 +/- 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 +/- 0.34 mg/dl versus 0.87 +/- 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.
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PMID:Deletion of the kinase domain in death-associated protein kinase attenuates tubular cell apoptosis in renal ischemia-reperfusion injury. 1521 70

We investigated the relevance of p53 deletions to the clinical outcome of patients with multiple myeloma (MM) treated with high-dose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by fluorescence in situ hybridization in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (P = .0062) and creatinine (P = .013) levels, but there were no association with patient age, gender, beta2-microglobulin, C-reactive protein, hemoglobin, albumin or bone lytic lesions, or immunoglobulin isotype. There were no associations of p53 deletions with 13q deletions or translocations t(11;14) or t(4;14). Patients with p53 deletions had significantly shorter progression-free (median, 7.9 versus 25.7 months, P = .0324) and overall survival (median, 14.7 versus 48.1 months, P = .0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression-free (P = .0009) or overall survival (P = .0002) in patients with MM after high-dose chemotherapy and autologous stem cell transplantation.
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PMID:p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. 1533 49

The apoptosis and the expression of tumor suppressor gene p53 in hypercholesterolemia (HC)-induced renal injury were investigated in rats. A high cholesterol diet (HCD)-induced HC rat model was made and serum lipid, urinary protein excretion (UPE) and N-aceto-beta-D-glucosidase (NAG) were measured. The levels of malondialdehyde (MDA), as an index of lipid peroxidation, in renal cortex and serum were compared between the two diet groups. Apoptosis and p53 expression were determined by TUNEL and immunohistochemistry, respectively. In the HCD-induced HC group, serum total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) as well as triglyceride (TG) were significantly increased, while the level of high density lipoprotein-cholesterol (HDL-C) decreased. Meanwhile, increased excretions of UPE and NAG in urine were observed, which were accompanied with a decrease in urinary creatinine clearance (Ccr) and indicated both glomerular and tubular damages. In addition, apoptotic cell death coexisted in the kidney, as revealed by increased TUNEL positive cells. Finally, an increase in p53 expression was observed in tubuli, but not in glomeruli. Both TUNEL, positive cells and p53 expression were found to be correlated to the level of renal cortical MDA (r = 0.817, P < 0.01 and r = 0.547, P < 0.01, respectively). The major manifestation of HCD-induced renal injury is apoptosis. The lipid peroxidation is a critical event to induce DNA damage and p53 is involved in the pathogenesis of lipid-induced renal injury.
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PMID:The p53-mediated apoptosis in hypercholesterolemia-induced renal injury of rats. 1619 89


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