LKB1 Is Recruited to the p21/WAF1 Promoter by p53 to Mediate Transcriptional Activation
| Autor: | Ping-Yao Zeng, Shelley L. Berger |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcriptional Activation congenital hereditary and neonatal diseases and abnormalities Cancer Research Tumor suppressor gene Protein Serine-Threonine Kinases Biology AMP-Activated Protein Kinase Kinases Humans Phosphorylation Promoter Regions Genetic skin and connective tissue diseases Cell Nucleus Regulation of gene expression Kinase G1 Phase Promoter Cell cycle CDKN1A Gene HCT116 Cells Molecular biology Gene Expression Regulation Neoplastic Oncology Tumor Suppressor Protein p53 Chromatin immunoprecipitation |
| Zdroj: | Cancer Research. 66:10701-10708 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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