CYCLIC-AMP-INDUCED G1 PHASE ARREST MEDIATED BY AN INHIBITOR (P27(KIP1)) OF CYCLIN-DEPENDENT KINASE-4 ACTIVATION
CYCLIC-AMP-INDUCED G1 PHASE ARREST MEDIATED BY AN INHIBITOR (P27(KIP1)) OF CYCLIN-DEPENDENT KINASE-4 ACTIVATION
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DOI：
10.1016/0092-8674(94)90257-7
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发表时间：
1994-11-04
期刊：
影响因子：
64.5
通讯作者：
SHERR, CJ
中科院分区：
文献类型：
--
作者：
KATO, JY;MATSUOKA, M;SHERR, CJ
环磷酸腺苷（cAMP）阻断巨噬细胞集落刺激因子1（CSF-1）的促有丝分裂作用，诱导细胞周期停滞在中期G1期。细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（cdk 4）之间的复合物在生长停滞细胞中组装，但cdk 4在体内不被cdk激活激酶（CAK）磷酸化，保持无活性。尽管在cAMP处理的细胞的裂解液中检测不到，但抗体沉淀后回收了活性CAK，这表明它不是抑制的直接靶点。cAMP处理的细胞中cdk抑制剂p27（Kip 1）的水平增加，其从抑制性裂解物中的免疫耗竭恢复CAK介导的cdk 4活化。Kip 1不与CAK结合，但其与细胞周期蛋白D-cdk 4的结合阻止CAK磷酸化和激活全酶。
Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 phase. Complexes between cyclin D1 and cyclin-dependent kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27(Kip1) increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.