期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 21, 期 9, 页码 3057-3070出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.9.3057-3070.2001
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资金
- NCI NIH HHS [R01CA70897, 5-P30-CA13330-26, R01CA75503, R01 CA77552, P30 CA013330, R01 CA075503] Funding Source: Medline
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-regulated nuclear receptor superfamily member, Liganded PPAR gamma exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPAR gamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPAR gamma ligands on cellular proliferation. Recent findings that PPAR gamma ligands convey PPAR gamma -independent activities through I kappaB kinase (IKK) raises important questions about the specific mechanisms through which PPAR gamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPAR gamma. Herein PPAR gamma, liganded by either natural (15d-PGJ(2) and PGD(2)) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin Hi-dependent serine-threonine kinase (Cdk) by 15d-PGJ(2) was not observed in PPAR gamma -deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ(2). Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPAR gamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin DI. Cyclin D1 repression by PPAR gamma involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ(2) enhanced recruitment of p300 to PPAR gamma but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects mag improve the utility of COX2 inhibitors.
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