Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4
Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4
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DOI：
10.1038/sj.onc.1203585
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发表时间：
2000-06-01
期刊：
影响因子：
8
通讯作者：
Burakoff, SJ
中科院分区：
文献类型：
--
作者：
Baksh, S;DeCaprio, JA;Burakoff, SJ
细胞周期蛋白依赖性激酶4(CDK8)的活性受调节亚基和抑制因子的结合以及酪氨酸和丝氨酸/苏氨酸磷酸化的控制，最近证实了钙水平的影响。通过瞬时转染Jurkat细胞，我们观察到CDK4与钙和钙调蛋白激活的丝氨酸/苏氨酸磷酸酶、钙调神经磷酸酶的特异性结合。此外，我们还证明了FK506和环孢菌素A抑制钙调神经磷酸酶的磷酸酶活性导致了CDK4激酶活性的整体增加，这表明钙调神经磷酸酶的活性对CDKA的活性有抑制作用。相反，我们没有观察到对CDK6或CDK2的磷酸酶活性的类似的影响，这表明钙调神经磷酸酶的活性是CDK4所特有的。此外，我们还观察到外源加入钙调神经磷酸酶导致了CDK4的去磷酸化，这一事件下调了CDK4Calcineurin的激酶活性，从而起到了与周期激活复合体相反的作用。一种上调CDK4的激酶活性的酶，CDK4是哺乳动物细胞中一种重要的G(0)/G(1)检查点元件。
Cyclin dependent kinase 4 (cdk8) activity is controlled by the binding of regulatory subunits and inhibitory factors, as well as tyrosine and serine/threonine phosphorylation, More recently the influence of calcium levels have been demonstrated. Using transient transfections in Jurkat cells, we observed specific binding between cdk4 and the calcium and calmodulin activated serine/threonine phosphatase, calcineurin. Furthermore, we demonstrated that the inhibition of the phosphatase activity of calcineurin with FK506 and cyclosporin A resulted in an overall increase in cdk4 kinase activity, suggesting that the phosphatase activity of calcineurin was inhibitory to the kinase activity of cdkA In contrast, we were not able to observe a similar effect on the kinase activity of either cdk6 or cdk2, indicating that the phosphatase activity of calcineurin was specific for cdk4, In addition, using an in vitro phosphatase assay for calcineurin, we observed that the exogenous addition of calcineurin resulted in the dephosphorylation of cdk4, an event that downregulated the kinase activity of cdk4 Calcineurin could, therefore, play an opposing role to the action of the cyclin activating kinase complex, an enzyme that upregulates the kinase activity of cdk4, an important G(0)/G(1) checkpoint element in mammalian cells.