BCL-xL and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases
BCL-xL and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases
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DOI：
10.1038/sj.onc.1205928
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发表时间：
2002-11-07
期刊：
影响因子：
8
通讯作者：
Yang, E
中科院分区：
文献类型：
--
作者：
Greider, C;Chattopadhyay, A;Yang, E
抗凋亡分子BCL-X-L和BCL 2延迟细胞从静止进入周期。我们使用血清诱导和静止成纤维细胞中Myc-雌激素受体融合蛋白（MycER）的诱导来研究BCL-X-L和BCL 2的细胞周期活性的机制。我们首次证明BCL-x（L）和BCL 2延迟血清诱导和Myc诱导的细胞周期进入，但不延迟E2 F诱导的细胞周期进入。在BCL-X-L或BCL 2表达的NIH 3 T3细胞和Rat 1 MycER细胞系中，细胞周期蛋白依赖性激酶抑制剂p27在血清剥夺和细胞周期进入期间升高。细胞周期蛋白依赖性激酶2（cdk 2）和细胞周期蛋白依赖性激酶4（cdk 4）的激活在进展到S期的过程中被延迟，而细胞周期蛋白131蛋白的诱导，以及细胞周期蛋白E，cdk 2和cdk 4的水平没有被BCL-X-L或BCL 2改变。在BCL-X-L或BCL 2表达细胞中，细胞周期蛋白/cdk活性的抑制与细胞周期蛋白/cdk复合物中过量的p27相关。BCL-X-L和BCL 2都不延迟p27缺陷细胞进入S期，因此p27是BCL-X-L和BCL 2的细胞周期功能所必需的。BCL-X-L和BCL 2在Myc诱导的细胞周期进入中的作用比在血清诱导的细胞周期进入中的作用更显著。我们的研究结果表明，BCL-X-L和BCL 2延迟细胞周期进入的一个可能机制可能是通过升高p27抑制Myc活性。
The anti-apoptotic molecules BCL-X-L and BCL2 delay cell cycle entry from quiescence. We used serum induction and induction of a Myc-estrogen receptor fusion protein (MycER) in quiescent fibroblasts to investigate the mechanisms underlying the cell cycle activity of BCL-X-L and BCL2. We demonstrate for the first time that BCL-x(L) and BCL2 delayed serum-induced and Myc-induced, but not E2F-induced, cell cycle entry. The cyclin-dependent kinase inhibitor p27 was elevated during serum deprivation and cell cycle entry in BCL-X-L or BCL2-expressing NIH3T3 cells and a Rat1MycER cell line. Activation of cyclin-dependent kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) were delayed during progression to S phase, while the induction of cyclin 131 protein, as well as the levels of cyclin E, cdk2, and cdk4 were unaltered by BCL-X-L or BCL2. Inhibition of cyclin/cdk activities in BCL-X-L or BCL2 expressing cells was associated with excess p27 in the cyclin/cdk complexes. Neither BCL-X-L nor BCL2 delayed S phase entry in cells deficient in p27, thus p27 is required for the cell cycle function of BCL-X-L and BCL2. The cell cycle effects of BCL-X-L and BCL2 were more profound in Myc-induced than in serum-induced cell cycle entry. Our results suggest that one possible mechanism by which BCL-X-L and BCL2 delay cell cycle entry may be the inhibition of Myc activity through the elevation of p27.