Identification and characterization of Bmi-1-responding element within the human p16 promoter

Sha Meng, Min Luo, He Sun, Xin Yu, Meili Shen, Quancang Zhang, Rudan Zhou, Xiaofang Ju, Wei Tao, Di Liu, Hongkui Deng, Zhigang Lu

Research output: Contribution to journalArticle

41 Scopus citations

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 p19Arf, 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.

Original languageEnglish (US)
Pages (from-to)33219-33229
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number43
DOIs
StatePublished - Oct 22 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Identification and characterization of Bmi-1-responding element within the human p16 promoter'. Together they form a unique fingerprint.

  • Cite this

    Meng, S., Luo, M., Sun, H., Yu, X., Shen, M., Zhang, Q., Zhou, R., Ju, X., Tao, W., Liu, D., Deng, H., & Lu, Z. (2010). Identification and characterization of Bmi-1-responding element within the human p16 promoter. Journal of Biological Chemistry, 285(43), 33219-33229. https://doi.org/10.1074/jbc.M110.133686