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首页> 外文期刊>Molecular and Cellular Biology >Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation
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Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

机译：过氧化物酶体增殖物激活的受体γ表达和反式激活的细胞周期蛋白D1抑制。

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The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPARγ induces hepatic steatosis, and liganded PPARγ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPARγ function, transactivation, expression, and promoter activity. PPARγ transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPARγ ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPARγ-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1?/? fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPARγ ligands of PPARγ and PPARγ-responsive genes, and cyclin D1?/? mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPARγ in vivo. The inhibition of PPARγ function by cyclin D1 is a new mechanism of signal transduction cross talk between PPARγ ligands and mitogenic signals that induce cyclin D1.
机译： cyclin D1 基因在人类乳腺癌中过表达，是癌基因诱导的肿瘤发生所必需的。过氧化物酶体增殖物激活受体γ（PPARγ）是被噻唑烷二酮类配体选择性激活的核受体。 PPARγ诱导肝脂肪变性，配体PPARγ促进脂肪细胞分化。在本文中，细胞周期蛋白D1抑制配体诱导的PPARγ功能，反式激活，表达和启动子活性。配体BRL49653诱导的PPARγ反式激活被细胞周期蛋白D1通过pRB和cdk独立机制抑制，需要预测一个形成螺旋-环-螺旋（HLH）结构的区域。还需要细胞周期蛋白D1 HLH区来抑制与异源DNA结合域连接的PPARγ配体结合域。细胞周期蛋白D1 ？/？ 成纤维细胞中PPARγ特异性配体（BRL49653，曲格列酮）对脂肪细胞的分化作用增强，而细胞周期蛋白D1的逆转录病毒表达则逆转了脂肪细胞的分化。 cyclin D1 基因的纯合缺失，PPARγ和PPARγ响应基因的PPARγ配体增强的表达以及 cyclin D1 ？/？ 小鼠表现出肝脂肪变性。最后，使用ponasterone诱导的cyclin D1反义转基因小鼠体内降低cyclin D1的丰度，可以提高体内PPARγ的表达。细胞周期蛋白D1对PPARγ功能的抑制是PPARγ配体与诱导细胞周期蛋白D1的有丝分裂信号之间信号转导串扰的新机制。

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