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

被引:155
作者
Lai, A
Kennedy, BK
Barbie, DA
Bertos, NR
Yang, XJ
Theberge, MC
Tsai, SC
Seto, E
Zhang, Y
Kuzmichev, A
Lane, WS
Reinberg, D
Harlow, E
Branton, PE
机构
[1] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[2] McGill Univ, Dept Oncol, Montreal, PQ H3G 1Y6, Canada
[3] McGill Univ, Mol Oncol Grp, Dept Med, Montreal, PQ H3G 1Y6, Canada
[4] MGH Canc Ctr, Charlestown, MA 02129 USA
[5] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem, Howard Hughes Med Inst,Div Nucle Acids Enzymol, Piscataway, NJ 08854 USA
[6] Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[7] Univ S Florida, Mol Oncol Program, H Lee Moffit Canc Ctr & Res Inst, Tampa, FL 33612 USA
[8] Harvard Univ, Harvard Microchem Facil, Cambridge, MA 02138 USA
关键词
D O I
10.1128/MCB.21.8.2918-2932.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2918 / 2932
页数:15
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