Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes
Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes
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DOI：
10.1128/mcb.18.2.753
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发表时间：
1998-02-01
影响因子：
5.3
通讯作者：
Weinberg, RA
中科院分区：
文献类型：
--
作者：
Lundberg, AS;Weinberg, RA
视网膜母细胞瘤蛋白（pRb）在哺乳动物细胞中抑制G(1)-S转化。G(1)中pRb的磷酸化使其生长抑制功能失活，允许细胞周期进展。尽管一些细胞周期蛋白和相关的细胞周期蛋白依赖性激酶（cdks）与pRb磷酸化有关，但pRb在体内磷酸化的确切机制尚不清楚。通过选择性抑制cdk4/6或cdk2，我们发现内源性d型细胞周期蛋白与cdk4/6一起作用，只能部分磷酸化pRb，这一过程可能由细胞周期蛋白E-cdk2复合物完成。此外，在没有细胞周期蛋白D-cdk4/6复合物磷酸化的情况下，周期蛋白E-cdk2不能磷酸化pRb。pRb的完全磷酸化、E2F结合的失活和E2F转录的激活只有在至少两个不同的G(1)细胞周期蛋白激酶复合物连续作用后才会发生。
The retinoblastoma protein (pRb) acts to constrain the G(1)-S transition in mammalian cells. Phosphorylation of pRb in G(1) inactivates its growth-inhibitory function, allowing for cell cycle progression. Although several cyclins and associated cyclin-dependent kinases (cdks) have been implicated in pRb phosphorylation, the precise mechanism by which pRb is phosphorylated in vivo remains unclear. By inhibiting selectively either cdk4/6 or cdk2, we show that endogenous D-type cyclins,acting with cdk4/6, are able to phosphorylate pRb only partially, a process that is likely to be completed by cyclin E-cdk2 complexes. Furthermore, cyclin E-cdk2 is unable to phosphorylate pRb in the absence of prior phosphorylation by cyclin D-cdk4/6 complexes. Complete phosphorylation of pRb, inactivation of E2F binding, and activation of E2F transcription occur only after sequential action of at least two distinct G(1) cyclin kinase complexes.