RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest
RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest
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DOI：
10.1128/mcb.21.8.2918-2932.2001
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发表时间：
2001-04-01
影响因子：
5.3
通讯作者：
Branton, PE
中科院分区：
文献类型：
--
作者：
Lai, A;Kennedy, BK;Branton, PE
视网膜母细胞瘤（RE）肿瘤抑制家族口袋蛋白通过组蛋白脱乙酰酶（HDAC）依赖性和非依赖性机制抑制E2 F调节基因的转录诱导细胞周期停滞。在这项研究中，我们已经确定了一个稳定的复合物，占招聘的镇压活动的口袋。这种复合物的一个组成部分是REP 1，一种已知的口袋结合蛋白，表现出HDAC依赖性和非依赖性抑制功能。RE家族蛋白显示通过口袋与先前鉴定的仅含有I类HDAC的mSIN 3-SAP 30-HDAC复合物缔合。这些酶不直接与RE家族蛋白相互作用，而是利用RBP 1靶向口袋。这种机制被证明是占大多数RE相关的HDAC活性。我们还表明，在静止的正常人细胞中，整个RBP 1-mSIN 3-SAP 30-HDAC复合物与RE家族成员和E2 F4共定位在细胞核的有限数量的离散区域中，在其他研究中已被证明代表生长刺激后DNA复制的初始起点。这些结果表明，RE家族成员，至少部分地，驱动退出细胞周期的招聘HDAC复合物通过REP 1抑制转录E2 F依赖性启动子，并可能改变染色质结构的DNA起源。
Retinoblastoma (RE) tumor suppressor family pocket proteins induce cell cycle arrest by repressing transcription of E2F-regulated genes through both histone deacetylase (HDAC)-dependent and -independent mechanisms. In this study we have identified a stable complex that accounts for the recruitment of both repression activities to the pocket. One component of this complex is REP1, a known pocket-binding protein that exhibits both HDAC-dependent and -independent repression functions. RE family proteins were shown to associate via the pocket with previously identified mSIN3-SAP30-HDAC complexes containing exclusively class I HDACs. Such enzymes do not interact directly with RE family proteins but rather utilize RBP1 to target the pocket. This mechanism was shown to account for the majority of RE-associated HDAC activity. We also show that in quiescent normal human cells this entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with both RE family members and E2F4 in a limited number of discrete regions of the nucleus that in other studies have been shown to represent the initial origins of DNA replication following growth stimulation. These results suggest that RE family members, at least in part, drive exit from the cell cycle by recruitment of this HDAC complex via REP1 to repress transcription from E2F-dependent promoters and possibly to alter chromatin structure at DNA origins.