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)

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The objectives of the present study were to characterize apoptosis regulation in primary mouse hepatocytes and to determine whether nongenotoxic carcinogens alter apoptosis regulation. Bleomycin-induced apoptosis was accompanied by decreases in bcl-2 and bcl-xl and increases in p53, bak, and bax protein levels. Transforming growth factor (TGF)-beta-induced apoptosis was accompanied by decreased bcl-xL and increased bak. Bleomycin-induced apoptosis was partially dependent on p53, whereas TGF-beta-induced apoptosis was independent of p53. Phenobarbital inhibited both TGF-beta and bleomycin-induced apoptosis and the normal regulation of p53, bcl-2, and bax. Nafenopin inhibited apoptosis through a mechanism dependent on PPAR-alpha and inhibited the normal regulation of bcl-2 and bak. 2,3,7,8-Tetrachlorodibenzo-p-dioxin did not alter apoptosis or its regulation. Apoptosis was increased in hepatocytes from bcl-2-null mice, which indicated that the bcl-2 family contributes to hepatocyte apoptosis regulation. This study demonstrated that apoptosis regulation in mouse hepatocytes involves distinct pathways and that diverse nongenotoxic carcinogens differentially alter molecular pathways that represent targets for hepatocarcinogenesis.
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PMID:Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens. 975 Nov 25

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The proto-oncogene c-myc has been shown to be important in apoptosis regulation and to be amplified and overexpressed in human and rodent liver neoplasia. The objectives of the study reported here were to determine whether apoptosis regulation is altered in transgenic hepatocytes that overexpress c-myc and whether growth factors or nongenotoxic carcinogens alter apoptosis regulation in c-myc versus wild-type hepatocytes. Hepatocytes isolated from c-myc transgenic mice had four fold more c-myc RNA and protein (at 12-48 h) in addition to increased apoptosis levels compared with wild-type hepatocytes. The increased apoptosis in c-myc hepatocytes was accompanied by increased p53, bax, and bak and decreased bcl-2 protein levels. Hepatocytes overexpressing c-myc were more sensitive to apoptosis induced by bleomycin but less sensitive to apoptosis induced by transforming growth factor (TGF)-beta. Phenobarbital, a potent liver tumor promoter, inhibited apoptosis in c-myc hepatocytes but not in wild-type hepatocytes, decreased p53 and bax, and increased bcl-2 protein levels. Nafenopin inhibited apoptosis in both c-myc and wild-type hepatocytes, whereas 2,3,7,8-tetrachlorodibenzo-pdioxin did not inhibit apoptosis in either wild-type or c-myc hepatocytes. TGF-alpha inhibited apoptosis and increased bcl-X(L) and decreased bak protein levels in c-myc hepatocytes but not in wild-type hepatocytes. Insulin-like growth factor-II did not affect apoptosis in c-myc or wild-type hepatocytes. In this study, overexpression of c-myc altered the response to apoptotic stimuli in transgenic hepatocytes. Furthermore, phenobarbital and TGF-alpha inhibited c-myc-induced apoptosis, which may have resulted in a selective growth advantage for an initiated cell population and which may be a mechanism for tumor promotion.
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PMID:Dysregulation of apoptosis by c-myc in transgenic hepatocytes and effects of growth factors and nongenotoxic carcinogens. 1044 34