Role of p27(Kip1) as a transcriptional regulator.
Role of p27(Kip1) as a transcriptional regulator.
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p27（KIP1）作为转录调节剂的作用。
DOI：
10.18632/oncotarget.25447
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发表时间：
2018-05-25
期刊：
影响因子：
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通讯作者：
Pujol MJ
中科院分区：
文献类型：
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作者：
Bachs O;Gallastegui E;Orlando S;Bigas A;Morante-Redolat JM;Serratosa J;Fariñas I;Aligué R;Pujol MJ
蛋白质 p27Kip1 是细胞周期蛋白依赖性激酶 (Cdk) 抑制剂 Cip/Kip 家族的成员。它与催化亚基和调节亚基（细胞周期蛋白）相互作用，并将一个区域引入 Cdk 的催化裂解中，从而诱导其失活。其抑制能力可以通过特定的酪氨酸磷酸化来调节。 p27Kip1 还充当转录调节因子。它通过不同的转录因子与特定的染色质结构域相关联。芯片上 ChIP、ChIP-seq 和表达微阵列分析可以鉴定 p27Kip1 调控的转录程序。因此，细胞分裂周期、呼吸、RNA 加工、翻译和细胞粘附等重要的细胞功能均受到 p27Kip1 的调节。此外，与癌症和神经退行性疾病等病理相关的基因也受到 p27Kip1 的调节，表明其在这些病理中的作用。 p27Kip1 的羧基部分可以与不同的蛋白质结合，包括转录调节因子。相反，其 NH2 末端区域与细胞周期蛋白-Cdk 复合物特异性相互作用。 p27Kip1 调节转录的一般机制模型是，它通过其 COOH 区域与染色质上的转录调节因子相关联，并通过 NH2 结构域与细胞周期蛋白-Cdk 复合物相关联。 Cdk 激活后，它会磷酸化染色质上的特定靶标，从而导致基因表达。该模型已被证明适用于参与细胞周期进展的 p130/E2F4 抑制基因的转录调控。我们在这篇综述中总结了我们目前对 p27Kip1 在转录调控中的作用、其调控下的转录程序及其与癌症和神经退行性疾病等病理学相关性的了解。
The protein p27Kip1 is a member of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors. It interacts with both the catalytic and the regulatory subunit (cyclin) and introduces a region into the catalytic cleave of the Cdk inducing its inactivation. Its inhibitory capacity can be modulated by specific tyrosine phosphorylations. p27Kip1 also behaves as a transcriptional regulator. It associates with specific chromatin domains through different transcription factors. ChIP on chip, ChIP-seq and expression microarray analysis allowed the identification of the transcriptional programs regulated by p27Kip1. Thus, important cellular functions as cell division cycle, respiration, RNA processing, translation and cell adhesion, are under p27Kip1 regulation. Moreover, genes involved in pathologies as cancer and neurodegeneration are also regulated by p27Kip1, suggesting its implication in these pathologies. The carboxyl moiety of p27Kip1 can associate with different proteins, including transcriptional regulators. In contrast, its NH2-terminal region specifically interacts with cyclin-Cdk complexes. The general mechanistic model of how p27Kip1 regulates transcription is that it associates by its COOH region to the transcriptional regulators on the chromatin and by the NH2-domain to cyclin-Cdk complexes. After Cdk activation it would phosphorylate the specific targets on the chromatin leading to gene expression. This model has been demonstrated to apply in the transcriptional regulation of p130/E2F4 repressed genes involved in cell cycle progression. We summarize in this review our current knowledge on the role of p27Kip1 in the regulation of transcription, on the transcriptional programs under its regulation and on its relevance in pathologies as cancer and neurodegeneration.