期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 17, 页码 16927-16938出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M309045200
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资金
- NCI NIH HHS [R01CA70896, R01CA86071, R01CA86072, R01CA75503] Funding Source: Medline
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) following exposure to PPARgamma-specific ligands resulted in growth inhibition in various carcinoma cell lines. Our aim was to elucidate the pathway of PPARgamma2 activation-mediated modulation of cyclin D1 transcription in mouse hepatocytes. To address this we utilized stable control and PPARgamma hepatocyte cell lines created via retroviral overexpression utilizing AML-12 hepatocytes. Addition of PPARgamma ligand troglitazone (TZD) activated PPARgamma2 in proliferating hepatocytes and resulted in growth arrest accompanied by a down-regulation of proliferating cell nuclear antigen, cyclin D1, and beta-catenin expression. Furthermore activation of PPARgamma2 attenuated cyclin D1 promoter activity indicating a transcriptional regulation of cyclin D1. Since beta-catenin plays a pivotal role in regulating cyclin D1 transcription, we studied whether PPARgamma2-mediated inhibition of cyclin D1 transcription involved beta-catenin. Interestingly overexpression of either wild-type or S37A mutant beta-catenin was unable to rescue PPARgamma2-mediated suppression of cyclin D1 transcription, whereas overexpression of cAMP-response element-binding protein (CREB) was capable of antagonizing this inhibitory effect of PPARgamma2. Additionally pretreatment with okadaic acid antagonized PPARgamma2-mediated inhibition of cyclin D1 transcription without any effect on beta-catenin expression. These studies also showed a TZD-mediated inhibition of total and phospho-CREBSer133 levels, CREB promoter activity, and cAMP-response element-mediated transcription in PPARgamma hepatocytes. Pretreatment of PPARgamma hepatocytes with okadaic acid, however, maintained higher total and phospho-CREBSer133 levels in the presence of TZD. These results indicated that PPARgamma2 activation inhibited cyclin D1 transcription in hepatocytes via CREB-dependent and beta-catenin-independent pathways.
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