BRG1 controls the activity of the retinoblastoma protein via regulation of p21CIP1/WAF1/SDI
BRG1 controls the activity of the retinoblastoma protein via regulation of p21CIP1/WAF1/SDI
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DOI：
10.1128/mcb.24.3.1188-1199.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Zhao, KJ
中科院分区：
文献类型：
--
作者：
Kang, H;Cui, KR;Zhao, KJ
普遍存在的哺乳动物染色质重塑SWI/SNF样BAF复合物在肿瘤发生中起关键作用。这表明，BRG 1与视网膜母细胞瘤蛋白pRB的直接相互作用是通过pRB调节细胞周期进程所必需的。我们提出的证据表明，BRG 1的复合物调节cdk抑制剂p21（CIP 1/WAF 1/SDI）的表达。此外，我们表明，BRG 1和pRB之间的物理相互作用是不需要诱导细胞生长停滞和转录抑制E2 F靶基因的pRB。相反，BRG 1通过上调cdk抑制剂p21诱导pRB的低磷酸化来激活pRB。pRB的低磷酸化通过下调pRB调控网络中的关键组分（包括cdk 2、细胞周期蛋白E和细胞周期蛋白D）而得到加强。我们证明，BRG 1上调p21是诱导扁平细胞形成、生长停滞和最终细胞衰老所必需的。我们的研究结果表明，含有BRG 1的复合物通过多种机制调节pRB通路来控制细胞增殖和衰老。
The ubiquitous mammalian chromatin-remodeling SWI/SNF-like BAF complexes play critical roles in tumorigenesis. It was suggested that the direct interaction of BRG1 with the retinoblastoma protein pRB is required for regulation of cell cycle progression by pRB. We present evidence that the BRG1-containing complexes regulate the expression of the cdk inhibitor p21(CIP1/WAF1/SDI). Furthermore, we show that the physical interaction between BRG1 and pRB is not required for induction of cell growth arrest and transcriptional repression of E2F target genes by pRB. Instead, BRG1 activates pRB by inducing its hypophosphorylation through up-regulation of the cdk inhibitor p21. The hypophosphorylation of pRB is reinforced by down-regulation of critical components, including cdk2, cyclin E, and cyclin D, in the pRB regulatory network. We demonstrate that up-regulation of p21 by BRG1 is necessary to induce formation of flat cells, growth arrest, and finally, cell senescence. Our results suggest that the BRG1-containing complexes control cellular proliferation and senescence by modulating the pRB pathway via multiple mechanisms.