Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5
Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5
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DOI：
10.1128/mcb.22.16.5975-5988.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Kalpana, GV
中科院分区：
文献类型：
--
作者：
Zhang, ZK;Davies, KP;Kalpana, GV
INI1/hSNF5是依赖于ATP的染色质重塑hSWI/SNF复合体的一个组成部分，也是儿童侵袭性非典型畸胎样和恶性横纹肌样肿瘤(AT/RT)的抑癌基因。为了了解其肿瘤抑制功能的分子机制，我们研究了INI1/hSNF5重新导入携带INI1/hSNF5双等位基因缺失的AT/RT来源的细胞系(如MON)的效果。我们证明INI1/hSNF5的表达导致这些细胞中GO-G、停滞和扁平细胞的形成。此外，INI1/hSNF5以组蛋白脱乙酰酶(HDAC)依赖的方式抑制MON细胞周期蛋白D1基因的转录。染色质免疫沉淀研究表明，INI1/hSNF5被直接招募到细胞周期蛋白D1启动子上，其结合与HDAC1的募集和组蛋白在启动子上的脱乙酰基有关。对INI1/hSNF5截断的分析表明，细胞周期蛋白D1的抑制与扁平细胞的形成密切相关。异源启动子共表达细胞周期蛋白D1足以消除INI1介导的扁平细胞形成和细胞周期停滞。此外，Cyclin D1在AT/RT肿瘤中高表达。我们的数据表明，INI1/hSNF5发挥肿瘤抑制作用的机制之一是通过直接将HDAC活性募集到细胞周期蛋白D1启动子而导致细胞周期停滞，从而导致其抑制和GO-G停滞。抑制细胞周期蛋白D1基因的表达可能成为治疗AT/RT的有效策略。
INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex and a tumor suppressor gene of aggressive pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT). To understand the molecular mechanisms underlying its tumor suppressor function, we studied the effect of reintroduction of INI1/hSNF5 into AT/RT-derived cell lines such as MON that carry biallelic deletions of the INI1/hSNF5 locus. We demonstrate that expression of INI1/hSNF5 causes GO-G, arrest and flat cell formation in these cells. In addition, INI1/hSNF5 repressed transcription of cyclin D1 gene in MON, in a histone deacetylase (HDAC)-dependent manner. Chromatin immunoprecipitation studies revealed that INI1/hSNF5 was directly recruited to the cyclin D1 promoter and that its binding correlated with recruitment of HDAC1 and deacetylation of histones at the promoter. Analysis of INI1/hSNF5 truncations indicated that cyclin D1 repression and flat cell formation are tightly correlated. Coexpression of cyclin D1 from a heterologous promoter in MON was sufficient to eliminate the INI1-mediated flat cell formation and cell cycle arrest. Furthermore, cyclin D1 was overexpressed in AT/RT tumors. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and GO-G, arrest. Repression of cyclin D1 gene expression may serve as a useful strategy to treat AT/RT.