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G1 细胞周期蛋白依赖性激酶足以启动静止人类成纤维细胞中的 DNA 合成。

G1 cyclin-dependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts.

作者信息

Connell-Crowley L, Elledge S J, Harper J W

机构信息

Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

出版信息

Curr Biol. 1998 Jan 1;8(1):65-8. doi: 10.1016/s0960-9822(98)70021-1.

Abstract

Mammalian fibroblasts require mitogens in order to exit from G0 (quiescence) and progress through the G1 phase of the cell cycle, although once they pass the restriction point late in G1 they can enter S phase and complete the cell cycle without mitogens [1]. Mitogenic signals are integrated through the GTPase Ras, which regulates the levels of cyclin D1 [2-5], a component of the cell cycle machinery that operates during G1 phase by activating cyclin-dependent kinase 4 (Cdk4). The accumulation of active cyclin E-Cdk2 complexes also requires Ras [6]. These two G1 cyclin-Cdk complexes act on a family of E2F-associated transcriptional repressors typified by the retinoblastoma protein (Rb) to bring about a transcriptional program that promotes passage through S phase [7-9], but can also activate DNA replication independently of Rb-E2F [10-12]. Although G1 cyclin-Cdk complexes are required for S-phase entry and can shorten G1 phase when overexpressed [13-15], it is not known whether they are sufficient for this transition. Here, we report that serum-starved (G0) diploid human fibroblasts initiate DNA synthesis upon microinjection of active G1 cyclin-Cdk complexes, but not upon microinjection of an S-phase cyclin-Cdk complex. These data indicate that G1 Cdk activation is rate-limiting for S-phase entry, and that Cdk activation is likely to be the primary function of growth factor signalling pathways that lead to DNA synthesis.

摘要

哺乳动物成纤维细胞需要有丝分裂原才能退出G0期(静止期)并进入细胞周期的G1期,不过一旦它们通过G1期后期的限制点,就可以在没有有丝分裂原的情况下进入S期并完成细胞周期[1]。有丝分裂信号通过GTP酶Ras整合,Ras调节细胞周期蛋白D1的水平[2-5],细胞周期蛋白D1是细胞周期机制的一个组成部分,在G1期通过激活细胞周期蛋白依赖性激酶4(Cdk4)发挥作用。活性细胞周期蛋白E-Cdk2复合物的积累也需要Ras[6]。这两种G1期细胞周期蛋白-Cdk复合物作用于以视网膜母细胞瘤蛋白(Rb)为代表的E2F相关转录抑制因子家族,从而引发一个促进通过S期的转录程序[7-9],但也可以独立于Rb-E2F激活DNA复制[10-12]。虽然G1期细胞周期蛋白-Cdk复合物是进入S期所必需的,并且在过表达时可以缩短G1期[13-15],但它们是否足以促成这种转变尚不清楚。在这里,我们报告血清饥饿(G0期)的二倍体人类成纤维细胞在显微注射活性G1期细胞周期蛋白-Cdk复合物后开始DNA合成,但在显微注射S期细胞周期蛋白-Cdk复合物后则不会。这些数据表明,G1期Cdk激活是进入S期的限速因素,并且Cdk激活可能是导致DNA合成的生长因子信号通路的主要功能。

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