Wang C, Fu M, D'Amico M, Albanese C, Zhou J N, Brownlee M, Lisanti M P, Chatterjee V K, Lazar M A, Pestell R G
Departments of Developmental and Molecular Biology and Medicine, The Albert Einstein Cancer Center, Bronx, New York 10461, USA.
Mol Cell Biol. 2001 May;21(9):3057-70. doi: 10.1128/MCB.21.9.3057-3070.2001.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARgamma 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 PPARgamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARgamma ligands on cellular proliferation. Recent findings that PPARgamma ligands convey PPARgamma-independent activities through IkappaB kinase (IKK) raises important questions about the specific mechanisms through which PPARgamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARgamma. Herein PPARgamma, 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 D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ(2) was not observed in PPARgamma-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 PPARgamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARgamma 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 PPARgamma but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.
核受体过氧化物酶体增殖物激活受体γ（PPARγ）是配体调节的核受体超家族成员。配体结合的PPARγ发挥多种生物学效应，促进脂肪细胞分化，抑制肿瘤细胞增殖，并在体外调节单核细胞/巨噬细胞及抗炎活性。对PPARγ配体的体内研究显示肿瘤生长增强，这增加了免疫功能降低和肿瘤监测可能超过PPARγ配体对细胞增殖的直接抑制作用的可能性。最近的研究发现PPARγ配体通过IκB激酶（IKK）传递不依赖PPARγ的活性，这引发了关于PPARγ配体抑制细胞增殖的具体机制的重要问题。我们研究了调节PPARγ抗增殖作用的机制。在此，由天然配体（15d-PGJ₂和PGD₂）或合成配体（BRL49653和曲格列酮）结合的PPARγ选择性抑制细胞周期蛋白D1基因的表达。在PPARγ缺陷细胞中未观察到15d-PGJ₂对S期进入和细胞周期蛋白D1依赖性丝氨酸 - 苏氨酸激酶（Cdk）活性的抑制作用。细胞周期蛋白D1的过表达逆转了15d-PGJ₂对S期的抑制作用。细胞周期蛋白D1的抑制独立于IKK，因为结合PPARγ但缺乏IKK相互作用环戊酮环羰基的前列腺素（PGs）可抑制细胞周期蛋白D1。PPARγ对细胞周期蛋白D1的抑制涉及通过细胞周期蛋白D1启动子的c-Fos结合位点竞争有限的p300丰度。15d-PGJ₂增强了p300与PPARγ的结合，但减少了与c-Fos的结合。类花生酸调节抗炎和抗增殖作用的不同途径的鉴定可能会提高COX2抑制剂的效用。
