LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation
LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation
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DOI：
10.1158/0008-5472.can-06-0999
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Berger, Shelley L.
中科院分区：
文献类型：
--
作者：
Zeng, Ping-Yao;Berger, Shelley L.
肿瘤抑制因子LKB 1是一种进化上保守的丝氨酸/苏氨酸激酶。在人类中，LKB 1可以通过导致Peutz-Jeghers综合征的种系突变或通过导致多种散发性癌症易感性的体细胞突变而失活。LKB 1具有广泛的功能，涉及肿瘤抑制和细胞稳态，包括建立细胞极性，设置能量代谢平衡（通过AMP依赖性激酶的磷酸化），调节细胞周期，并促进凋亡。LKB 1的功能以前与肿瘤抑制基因p53有关，并显示激活p53靶基因p21/WAF 1。在这项研究中，我们进一步研究了LKB 1激活p21/WAF 1基因，并解决了LKB 1是否直接参与基因启动子。我们发现，与以前的研究一致，LKB 1在体内稳定p53，与p21/WAF 1的激活相关。我们发现LKB 1与细胞核中的p53物理结合，并直接或间接磷酸化p53 Ser 15（以前被AMP依赖性激酶磷酸化）和p53 Ser 392。此外，这两个p53残基是LKB 1依赖性细胞周期G阻滞所必需的。染色质免疫沉淀分析表明，LKB 1直接募集到p21/WAF 1启动子，以及其他p53激活的启动子，在p53依赖的方式。最后，LKB 1与缺失其激活结构域的缺陷性p53的遗传融合促进p21/WAF 1的激活。这些结果表明，LKB 1在p21/WAF 1基因的激活中起直接作用。
The tumor suppressor LKB1 is an evolutionarily conserved serine/threonine kinase. In humans, LKB1 can be inactivated either by germ-line mutations resulting in Peutz-Jeghers syndrome or by somatic mutations causing predisposition to multiple sporadic cancers. LKB1 has wide-ranging functions involved in tumor suppression and cell homeostasis, including establishing cell polarity, setting energy metabolic balance (via phosphorylation of AMP-dependent kinase), regulating the cell cycle, and promoting apoptosis. LKB1 function was previously linked to the tumor suppressor p53 and shown to activate the p53 target gene p21/WAF1. In this study, we further investigated LKB1 activation of the p21/WAF1 gene and addressed whether LKB1 is directly involved at the gene promoter. We find that, consistent with previous studies, LKB1 stabilizes p53 in vivo, correlating with activation of p21/WAF1. We show that LKB1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 Ser15 (previously shown to be phosphorylated by AMP-dependent kinase) and p53 Ser392. Further, these two p53 residues are required for LKB1-dependent cell cycle G, arrest. Chromatin immunoprecipitation analyses show that LKB1 is recruited directly to the p21/WAF1 promoter, as well as to other p53 activated promoters, in a p53-dependent fashion. Finally, a genetic fusion of LKB1 to defective p53, deleted for its activation domains, promotes activation of p21/WAF1. These results indicate that LKB1 has a direct role in activation of p21/WAF1 gene.