| Title | Identification and Characterization of Bmi-1-responding Element within the Human p16 Promoter |
| Authors | Meng, Sha Luo, Min Sun, He Yu, Xin Shen, Meili Zhang, Quancang Zhou, Rudan Ju, Xiaofang Tao, Wei Liu, Di Deng, Hongkui Lu, Zhigang |
| Affiliation | Chinese Acad Sci, Inst Microbiol, Network Informat Ctr, Beijing 100101, Peoples R China. Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Sch Chem Biol & Biotechnol, Shenzhen 518055, Peoples R China. Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. Chinese Acad Sci, Inst Genet & Dev Biol, Beijing 100101, Peoples R China. |
| Keywords | CELL SELF-RENEWAL HEMATOPOIETIC STEM-CELLS BMI-1 EXPRESSION P-GLYCOPROTEIN NEUROBLASTOMA-CELLS TELOMERASE ACTIVITY H2A UBIQUITYLATION TUMOR-SUPPRESSOR EPITHELIAL-CELLS INK4A/ARF LOCUS |
| Issue Date | 2010 |
| Publisher | journal of biological chemistry |
| Citation | JOURNAL OF BIOLOGICAL CHEMISTRY.2010,285,(43),33219-33229. |
| Abstract | Bmi-1, the first functionally identified polycomb gene family member, plays critical roles in cell cycle regulation, cell immortalization, and cell senescence. Bmi-1 is involved in the development and progression of carcinomas and is a potent target for cancer therapy. One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16(Ink4a) and p19(Arf), as Bmi-1 represses the INK4a locus on which they are encoded. A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear. In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter. The BRE resided at bp -821 to -732 upstream of the p16 ATG codon. BRE alone was sufficient to allow Bmi-1-mediated regulation of the CMV promoter. Bmi-1 typically functions by forming a complex with Ring2; however, regulation of p16 was independent of Ring2. Chromatin immunoprecipitation sequencing of Bmi-1-precipitated chromatin DNA revealed that 1536 genes were targeted by Bmi-1, including genes involved in tissue-specific differentiation, cell cycle, and apoptosis. By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation. Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy. |
| URI | http://hdl.handle.net/20.500.11897/344195 |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M110.133686 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 深圳研究生院待认领 生命科学学院 |
