Characterization of a new family of cyclin-dependent kinase activators
Characterization of a new family of cyclin-dependent kinase activators
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DOI：
10.1042/bj20041779
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发表时间：
2005-03-01
影响因子：
4.1
通讯作者：
Nebreda, AR
中科院分区：
文献类型：
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作者：
Dinarina, A;Perez, LH;Nebreda, AR
通过细胞周期的进展由CDK（细胞周期蛋白依赖性激酶）调节，其与称为细胞周期蛋白的活化配偶体结合以有效地磷酸化底物。我们以前报道的识别RINGO，爪蟾蛋白，可以激活CDK 1和CDK 2，尽管缺乏序列相似性的细胞周期蛋白，这在卵母细胞减数分裂细胞周期的调节中发挥作用。在本研究中，我们报告了四种哺乳动物RINGO蛋白的特征，它们与非洲爪蟾RINGO在约75个残基的中心核心中具有53- 68%的相同性。我们发现，所有RINGO家族成员都可以结合并激活CDK 1和CDK 2，尽管效率不同，但它们不结合CDK 4或CDK 6。核心RINGO序列对于CDK活化至关重要。我们还鉴定了RINGO结合所需的CDK 2中的关键残基。所有RINGO蛋白也可以结合CDK抑制剂P27（Kip 1），但其结合CDK 1的能力相反。我们的研究结果确定了一个新的哺乳动物蛋白家族，可以激活CDKs，因此可能作为细胞周期调节因子。RINGO蛋白激活CDK 1和CDK 2的能力也表明了这些激酶的细胞周期蛋白非依赖性作用。
Progression through the cell cycle is regulated by CDKs (cyclin-dependent kinases), which associate with activating partners, named cyclins, to efficiently phosphorylate substrates. We previously reported the identification of RINGO, a Xenopus protein that can activate CDK1 and CDK2 despite lack of sequence similarity to cyclins, which plays a role in the regulation of the meiotic cell cycle in oocytes. In the present study we report the characterization of four mammalian RINGO proteins, which are 53-68 % identical with Xenopus RINGO in a central core of about 75 residues. We show that all RINGO family members can bind to and activate CDK1 and CDK2, albeit with different efficiencies, but they do not bind to CDK4 or CDK6. The core RINGO sequences are critical for CDK activation. We also identified key residues in CDK2 that are required for RINGO binding. All RINGO proteins can also bind the CDK inhibitor P27(Kip1), but with an inverse efficiency of their ability to bind to CDK1. Our results identify a new family of mammalian proteins that can activate CDKs and therefore potentially function as cell cycle regulators. The ability of RINGO proteins to activate CDK1 and CDK2 suggest also cyclin-independent roles for these kinases.