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首页> 外文期刊>Molecular and Cellular Biology >The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene
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The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene

机译：肿瘤抑制因子p53和组蛋白去乙酰化酶1是细胞周期蛋白依赖性激酶抑制剂p21 / WAF1 / CIP1基因的拮抗调节剂。

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The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is an important regulator of cell cycle progression, senescence, and differentiation. Genotoxic stress leads to activation of the tumor suppressor p53 and subsequently to induction of p21 expression. Here we show that the tumor suppressor p53 cooperates with the transcription factor Sp1 in the activation of the p21 promoter, whereas histone deacetylase 1 (HDAC1) counteracts p53-induced transcription from the p21 gene. The p53 protein binds directly to the C terminus of Sp1, a domain which was previously shown to be required for the interaction with HDAC1. Induction of p53 in response to DNA-damaging agents resulted in the formation of p53-Sp1 complexes and simultaneous dissociation of HDAC1 from the C terminus of Sp1. Chromatin immunoprecipitation experiments demonstrated the association of HDAC1 with the p21 gene in proliferating cells. Genotoxic stress led to recruitment of p53, reduced binding of HDAC1, and hyperacetylation of core histones at the p21 promoter. Our findings show that the deacetylase HDAC1 acts as an antagonist of the tumor suppressor p53 in the regulation of the cyclin-dependent kinase inhibitor p21 and provide a basis for understanding the function of histone deacetylase inhibitors as antitumor drugs.
机译：细胞周期蛋白依赖性激酶抑制剂p21 / WAF1 / CIP1是细胞周期进程，衰老和分化的重要调节剂。基因毒性应激导致肿瘤抑制因子p53激活，并随后诱导p21表达。在这里，我们显示肿瘤抑制因子p53在激活p21启动子时与转录因子Sp1协同作用，而组蛋白脱乙酰基酶1（HDAC1）则抵消了p53诱导的p21基因转录。 p53蛋白直接结合到Sp1的C末端，该区域先前已显示是与HDAC1相互作用所必需的。响应DNA损伤剂而诱导p53导致形成p53-Sp1复合物，并同时使HDAC1从Sp1的C末端解离。染色质免疫沉淀实验表明，HDAC1与增殖细胞中的p21基因相关。基因毒性应激导致p53募集，HDAC1结合减少以及p21启动子上核心组蛋白的过度乙酰化。我们的发现表明，脱乙酰基酶HDAC1在细胞周期蛋白依赖性激酶抑制剂p21的调节中作为肿瘤抑制因子p53的拮抗剂，为理解组蛋白脱乙酰基酶抑制剂作为抗肿瘤药物的功能提供了基础。

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