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LKB1 Is Recruited to the p21/WAF1 Promoter by p53 to Mediate Transcriptional Activation

¹ Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania and ² Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, P.R. China

Requests for reprints: Shelley L. Berger, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-898-3922; Fax: 215-898-0663; E-mail: berger{at}wistar.upenn.edu.

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 G₁ 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. (Cancer Res 2006; 66(22): 10701-8)

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