Induction of cyclin D1 by simian virus 40 small tumor antigen.
Induction of cyclin D1 by simian virus 40 small tumor antigen.
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DOI：
10.1073/pnas.93.23.12861
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发表时间：
1996-11
影响因子：
11.1
通讯作者：
G. Watanabe;Alan K. Howe;Richard Lee;C. Albanese;I-Wei Shu;A. Karnezis;Leonard 1. Zon;J. Kyriakis;K. Rundell;R. Pestell
中科院分区：
文献类型：
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作者：
G. Watanabe;Alan K. Howe;Richard Lee;C. Albanese;I-Wei Shu;A. Karnezis;Leonard 1. Zon;J. Kyriakis;K. Rundell;R. Pestell
细胞周期进程由细胞周期蛋白依赖性激酶与其靶蛋白（包括pRB和E2 F/DP-1复合物）之间的协同相互作用介导。免疫中和和反义实验已经确定，丰富的细胞周期蛋白D1，调节亚基的细胞周期蛋白依赖性激酶，可能是限速的G1期进展的细胞周期。猴病毒40（SV 40）小肿瘤（t）抗原能够促进G1期进展，并通过几个不同的结构域显著提高SV 40转化的效率。在这些研究中，小t抗原刺激细胞周期蛋白D1启动子活性7倍，主要是通过AP-1结合位点在-954与额外的贡献从CRE位点在-57。当与异源启动子连接时，细胞周期蛋白D1 AP-1和CRE位点足以被小t抗原激活。小t抗原的点突变之间的残基97-103，减少PP 2A结合的诱导细胞周期蛋白D1启动子部分缺陷。这些突变还减少了转染细胞中MEK 1和促分裂原活化蛋白激酶家族的两个不同成员ERK（细胞外信号调节激酶）和SAPK（应激活化蛋白激酶）的活化。显性负突变体的MEK 1，ERK或SEK 1，减少小t依赖诱导的细胞周期蛋白D1启动子。细胞周期蛋白D1启动子的SV 40小t诱导涉及ERK和SAPK途径，它们一起可能有助于小t抗原的增殖和转化增强活性。
Cell-cycle progression is mediated by a co-ordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F/DP-1 complexes. Immunoneutralization and antisense experiments have established that the abundance of cyclin D1, a regulatory subunit of the cyclin-dependent kinases, may be rate-limiting for G1 phase progression of the cell cycle. Simian virus 40 (SV40) small tumor (t) antigen is capable of promoting G1 phase progression and augments substantially the efficiency of SV40 transformation through several distinct domains. In these studies, small t antigen stimulated cyclin D1 promoter activity 7-fold, primarily through an AP-1 binding site at -954 with additional contributions from a CRE site at -57. The cyclin D1 AP-1 and CRE sites were sufficient for activation by small t antigen when linked to an heterologous promoter. Point mutations of small t antigen between residues 97-103 that reduced PP2A binding were partially defective in the induction of the cyclin D1 promoter. These mutations also reduced activation of MEK1 and two distinct members of the mitogen-activated protein kinase family, the ERKs (extracellular signal regulated kinases) and the SAPKs (stress-activated protein kinases), in transfected cells. Dominant negative mutants of either MEK1, ERK or SEK1, reduced small t-dependent induction of the cyclin D1 promoter. SV40 small t induction of the cyclin D1 promoter involves both the ERK and SAPK pathways that together may contribute to the proliferative and transformation enhancing activity of small t antigen.