Tumor suppressor SMAR1 mediates cyclin D1 repression by recruitment of the SIN3/histone deacetylase 1 complex
Tumor suppressor SMAR1 mediates cyclin D1 repression by recruitment of the SIN3/histone deacetylase 1 complex
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DOI：
10.1128/mcb.25.19.8415-8429.2005
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发表时间：
2005-10-01
影响因子：
5.3
通讯作者：
Chattopadhyay, S
中科院分区：
文献类型：
--
作者：
Rampalli, S;Pavithra, L;Chattopadhyay, S
基质附着区结合蛋白已被证明在基因调控中发挥重要作用，通过阶段和组织特异性方式改变染色质。我们之前的研究报道了基质相关蛋白SMAR1在小鼠中消退b16 - f1诱导的肿瘤。在这里，我们发现SMAR1靶向细胞周期蛋白D1启动子，这是一种基因产物，其失调归因于乳腺恶性肿瘤。我们的研究表明，SMAR1可以抑制cyclin D1基因的表达，而这种抑制可以被SMAR1特异性的小干扰RNA逆转。我们证明SMAR1与组蛋白去乙酰化复合体1、SIN3和口袋视网膜母细胞瘤相互作用，形成多蛋白抑制复合体。这种相互作用是由SMAR1（160-350）结构域介导的。我们的数据表明，SMAR1向细胞周期蛋白D1启动子募集一个抑制复合物，导致该位点的染色质去乙酰化，并扩散到细胞周期蛋白D1启动子上游至少5kb的距离。有趣的是，我们发现乳腺癌细胞系中cyclin D1的高诱导可能与这些细胞系中SMAR1水平的降低有关。我们的研究结果确立了SMAR1通过修饰染色质调控cyclin D1的分子机制。
Matrix attachment region binding proteins have been shown to play an important role in gene regulation by altering chromatin in a stage- and tissue-specific manner. Our previous studies report that SMAR1, a matrix-associated protein, regresses B16-F1-induced tumors in mice. Here we show SMAR1 targets the cyclin D1 promoter, a gene product whose dysregulation is attributed to breast malignancies. Our studies reveal that SMAR1 represses cyclin D1 gene expression, which can be reversed by small interfering RNA specific to SMAR1. We demonstrate that SMAR1 interacts with histone deacetylation complex 1, SIN3, and pocket retinoblastomas to form a multiprotein repressor complex. This interaction is mediated by the SMAR1(160-350) domain. Our data suggest SMAR1 recruits a repressor complex to the cyclin D1 promoter that results in deacetylation of chromatin at that locus, which spreads to a distance of at least the 5 kb studied upstream of the cyclin D1 promoter. Interestingly, we find that the high induction of cyclin D1 in breast cancer cell lines can be correlated to the decreased levels of SMAR1 in these lines. Our results establish the molecular mechanism exhibited by SMAR1 to regulate cyclin D1 by modification of chromatin.