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首页> 外文期刊>Molecular and Cellular Biology >p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases.
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p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases.

机译：p21CIP1和Cdc25A：细胞周期蛋白依赖性激酶的抑制剂和激活剂之间的竞争。

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Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.
机译：Cdc25A，一种对G1-S过渡至关重要的磷酸酶，可与细胞周期激酶cyclin E-cdk2结合，去磷酸化并激活。 p21CIP1和p27是由生长抑制信号（例如p53和转化生长因子β（TGF-beta））诱导的细胞周期蛋白依赖性激酶（cdk）抑制剂。我们已经确定了Cdc25A N末端附近的细胞周期蛋白结合基序，该基序与cdk抑制剂p21CIP1家族的细胞周期蛋白结合Cy（或RR LFG）基序相似，并且与催化域分离。在体外和体内，该基序中的突变破坏了Cdc25A与细胞周期蛋白E-或细胞周期蛋白A-cdk2的结合，并选择性干扰细胞周期蛋白E-cdk2的去磷酸化。基于p21的Cy基序的肽竞争性破坏Cdc25A与细胞周期蛋白-cdks的结合，并抑制激酶的去磷酸化。 p21抑制Cdc25A-cyclin-cdk2缔合和cdk2的去磷酸化。相反，Cdc25A本身是Myc癌基因上调的癌基因，它与cyclin-cdk结合并保护其不受p21的抑制。 Cdc25A还保护非洲爪蟾卵提取物中的DNA复制不受p21的抑制。这些结果描述了一种机制，通过该机制，Myc或Cdc25A诱导的致癌作用和p53或TGF-β诱导的生长抑制途径通过竞争细胞周期蛋白cdks相互抵消。

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