P27(KIP1), A CYCLIN-CDK INHIBITOR, LINKS TRANSFORMING GROWTH-FACTOR-BETA AND CONTACT INHIBITION TO CELL-CYCLE ARREST
P27(KIP1), A CYCLIN-CDK INHIBITOR, LINKS TRANSFORMING GROWTH-FACTOR-BETA AND CONTACT INHIBITION TO CELL-CYCLE ARREST
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DOI：
10.1101/gad.8.1.9
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发表时间：
1994-01-01
影响因子：
10.5
通讯作者：
KOFF, A
中科院分区：
文献类型：
--
作者：
POLYAK, K;KATO, JY;KOFF, A
细胞 - 细胞接触和转化生长因子 -β（TGF -β）可使细胞周期停滞在G1期。因这两种机制中的任何一种而停滞的Mv1Lu貂上皮细胞无法组装含有G1期细胞周期蛋白（cyclin E）及其催化亚基Cdk2的活性复合物。这些生长抑制信号通过提高激活Cdk2所需的细胞周期蛋白E的阈值水平来阻断Cdk2的活化。在停滞的细胞中，该阈值设定得高于生理水平的细胞周期蛋白E，并且由一种与细胞周期蛋白E - Cdk2复合物结合的抑制剂所决定。利用细胞周期蛋白E - Cdk2亲和层析，可以从停滞的细胞中纯化出一种27 - kD的蛋白质，它能与细胞周期蛋白E - Cdk2复合物结合并阻止其活化，但在增殖细胞中则无法纯化得到。p27存在于增殖细胞中，但它被隔离，无法与细胞周期蛋白E - Cdk2复合物相互作用。细胞周期蛋白D2 - Cdk4复合物竞争性结合并下调p27的活性，因此可能在一条逆转Cdk2抑制并使细胞周期从G1期进展的途径中发挥作用。
Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.