ATM在丝氨酸202位点使ZBP - 89磷酸化，以增强丁酸盐对p21waf1的诱导作用。
ATM phosphorylates ZBP-89 at Ser202 to potentiate p21waf1 induction by butyrate.
作者信息
Bai Longchuan, Merchant Juanita L
机构信息
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
Biochem Biophys Res Commun. 2007 Aug 3;359(3):817-21. doi: 10.1016/j.bbrc.2007.05.197. Epub 2007 Jun 6.
Abstract
Histone deacetylase inhibitors (HDACi) induce growth arrest and differentiation, particularly in the colon where they are potential chemotherapeutic agents. A key mediator of HDACi action is the cyclin dependent kinase (CDK) inhibitor p21(waf1). HDACi treatment of colonic cells promotes the formation of an ATM/ZBP-89/p300 complex on p21(waf1) proximal promoter, and this multi-molecular complex plays an important role in HDACi induction of p21(waf1) expression in vitro and mucosal protection in vivo. Here we found that ZBP-89 is phosphorylated by ATM kinase in vitro and in vivo. Disruption of the ATM phosphorylation motif (202)SQ within the zinc finger domain of ZBP-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the ATM phosphorylation site abrogated the ability of ZBP-89 to potentiate butyrate induction of endogenous p21(waf1) expression. These results demonstrate that ATM phosphorylation of ZBP-89 contributes to HDACi induction of p21(waf1) gene expression.
摘要
组蛋白去乙酰化酶抑制剂（HDACi）可诱导细胞生长停滞和分化，在结肠中尤其如此，它们在结肠中是潜在的化疗药物。HDACi作用的一个关键介质是细胞周期蛋白依赖性激酶（CDK）抑制剂p21（waf1）。用HDACi处理结肠细胞可促进在p21（waf1）近端启动子上形成ATM/ZBP - 89/p300复合物，并且这种多分子复合物在体外HDACi诱导p21（waf1）表达和体内黏膜保护中起重要作用。在此我们发现ZBP - 89在体外和体内均可被ATM激酶磷酸化。破坏ZBP - 89锌指结构域内的ATM磷酸化基序（202）SQ会减弱其增强丁酸盐对p21（waf1）激活的能力。此外，破坏ATM磷酸化位点会消除ZBP - 89增强丁酸盐诱导内源性p21（waf1）表达的能力。这些结果表明ZBP - 89的ATM磷酸化有助于HDACi诱导p21（waf1）基因表达。
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