Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment
Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment
复制标题
DOI：
10.1074/jbc.m500403200
复制
发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Pestell, RG
中科院分区：
文献类型：
--
作者：
Fu, MF;Rao, M;Pestell, RG
细胞周期蛋白D1基因编码不稳定的血清诱导的调节亚基的全酶磷酸化和失活的视网膜母细胞瘤蛋白。细胞周期蛋白D1的过表达促进细胞增殖和正常生理水平的细胞周期蛋白D1功能，以抑制体内脂肪细胞分化。我们以前已经表明，细胞周期蛋白D1抑制过氧化物酶体增殖物激活受体（PPAR）γ依赖性活动，通过细胞周期蛋白依赖性激酶和视网膜母细胞瘤蛋白结合的独立机制。在这项研究中，我们确定了细胞周期蛋白D1调节PPAR γ功能的分子机制。在此，小鼠胚胎成纤维细胞（MEF）分化的过氧化物酶体增殖物激活受体γ配体与组蛋白脱乙酰酶（HDAC 1）活性的降低。细胞周期蛋白D1（-/-）MEFs表现出增加的倾向，经历分化成脂肪细胞。细胞周期蛋白D1的基因缺失降低了HDAC 1的活性。将细胞周期蛋白D1重组到细胞周期蛋白D1（-/-）MEFs中增加HDAC 1活性并阻断PPAR γ介导的脂肪生成。在cyclin D1（-/-）细胞中，PPAR γ活性增强。重新引入细胞周期蛋白D1抑制了基础和配体诱导的PPAR γ活性，并增强了HDAC对PPAR γ活性的抑制。细胞周期蛋白D1在体内结合HDAC，并优先与HDAC 1、HDAC 2、HDAC 3和HDAC 5物理结合。染色质免疫沉淀试验表明，细胞周期蛋白D1增强招聘HDAC 1和HDAC 3和组蛋白甲基转移酶SUV 39 H1的脂蛋白脂肪酶启动子的PPAR反应元件和减少乙酰化的总组蛋白H3和组蛋白H3赖氨酸9。总的来说，这些研究表明，细胞周期蛋白D1通过招募HDAC调节PPAR反应元件局部染色质结构和PPAR γ功能，在调节PPAR γ介导的脂肪细胞分化中发挥重要作用。
The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo. We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor ( PPAR) gamma-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism. In this study, we determined the molecular mechanism by which cyclin D1 regulated PPAR gamma function. Herein, murine embryonic fibroblast (MEF) differentiation by PPAR gamma ligand was associated with a reduction in histone deacetylase (HDAC1) activity. Cyclin D1(-/-) MEFs showed an increased propensity to undergo differentiation into adipocytes. Genetic deletion of cyclin D1 reduced HDAC1 activity. Reconstitution of cyclin D1 into the cyclin D1(-/-) MEFs increased HDAC1 activity and blocked PPAR gamma-mediated adipogenesis. PPAR gamma activity was enhanced in cyclin D1(-/-) cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPAR gamma activity and enhanced HDAC repression of PPAR gamma activity. Cyclin D1 bound HDAC in vivo and preferentially physically associated with HDAC1, HDAC2, HDAC3, and HDAC5. Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of HDAC1 and HDAC3 and histone methyltransferase SUV39H1 to the PPAR response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9. Collectively, these studies suggest an important role of cyclin D1 in regulation of PPAR gamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPAR gamma function.