Investigation of the cell cycle regulation of cdk3-associated kinase activity and the role of cdk3 in proliferation and transformation
Investigation of the cell cycle regulation of cdk3-associated kinase activity and the role of cdk3 in proliferation and transformation
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DOI：
10.1038/sj.onc.1202145
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发表时间：
1998-10-29
期刊：
影响因子：
8
通讯作者：
Hengstschläger, M
中科院分区：
文献类型：
--
作者：
Braun, K;Hölzl, G;Hengstschläger, M
哺乳动物细胞中的G1-S转变已经被证明需要细胞周期蛋白依赖性激酶cdk 2、cdk 3和cdk 4/6。在这里，我们表明，一种新的激酶活性与cdk 3波动在整个细胞周期不同的细胞周期蛋白D1，E-和A-相关的激酶活性的表达。Cdk 3激酶活性既不受p16（与cdk 4/6相反）的影响，也不受E2 F-1（与cdk 2相反）的影响，但在瞬时p27表达后下调。我们发现cdk 3与p21和p27结合，这为p27可能参与cdk 3活性的细胞周期波动的调节提供了证据：当cdk 3激酶在细胞周期中变得活跃时，cdk 3蛋白不波动，cdk 3与p27而不是与p21的相互作用丧失。在Myc过表达的细胞中，而不是在正常的Rat 1细胞中，cdk 3的组成性异位表达诱导cdk 3相关激酶活性的特异性上调，这仍然是细胞周期时相依赖的。异位cdk 3，而不是cdk 2，增强与Myc激活相关的Myc诱导的增殖和锚定非依赖性生长，而不影响细胞周期蛋白D1，E-和A蛋白表达或激酶活性。在Myc过表达细胞中高水平的cdk 3触发E2 F依赖性转录的上调和下调，而不诱导E2 F-DNA结合能力。与所有其他研究的阳性G1调节剂相反，cdk 3不能与ras在成纤维细胞转化中合作，这表明cdk 3在G1进展中的功能不同于细胞周期蛋白D或E相关激酶活性。我们的数据提供了第一次深入了解cdk 3相关激酶活性的调节，并提出了一个模型cdk 3如何参与G1-S转换的调节。
The G1-S transition in mammalian cells has been demonstrated to require the cyclin-dependent kinases cdk2, cdk3 and cdk4/6. Here we show that a novel kinase activity associated with cdk3 fluctuates throughout the cell cycle differently from the expression of cyclin D1-, E- and A-associated kinase activities. Cdk3 kinase activity is neither affected by p16 (in contrast to cdk4/6) nor by E2F-1 (in contrast to cdk2), but is downregulated upon transient p27 expression. We found cdk3 to bind to p21 and p27, We provide evidence that p27 could be involved in the regulation of the cell cycle fluctuation of cdk3 activity: cdk3 protein does not fluctuate and interaction of cdk3 with p27, but not with p21, is lost when cdk3 kinase becomes active during the cell cycle. In Myc-overexpressing cells, but not in normal Rat1 cells, constitutive ectopic expression of cdk3 induces specific upregulation of cdk3-associated kinase activity that is still cell cycle phase dependent. Ectopic cdk3, but not cdk2, enhances Myc-induced proliferation and anchorage-independent growth associated with Myc activation, without effects on cyclin D1, E- and A protein expression or kinase activities. High levels of cdk3 in Myc-overexpressing cells trigger up- and deregulation of E2F-dependent transcription without inducing the E2F-DNA binding capacity. In contrast to all other studied positive G1 regulators, cdk3 is unable to cooperate with ras in fibroblast transformation suggesting a function of cdk3 in G1 progression that is different from cyclin Dor E-associated kinase activities. Our data provide first insights into the regulation of cdk3-associated kinase activity and suggest a model how cdk3 participates in the regulation of the G1-S transition.