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  • The EMBO Journal (2009) 28, 2719 - 2732
  • doi:10.1038/emboj.2009.214

Published online: 20 August 2009

Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis

Hong-li Yan1, Geng Xue1, Qian Mei1, Yu-zhao Wang1, Fei-xiang Ding1, Mo-Fang Liu2, Ming-Hua Lu2, Ying Tang3, Hong-yu Yu4 and Shu-han Sun1

  1. Institute of Genetics, Second Military Medical University, Shanghai, China
  2. Institute of Biochemistry and Cell Biology, The Chinese Academy of Sciences, Shanghai, China
  3. Department of cell biology, Second Military Medical University, Shanghai, China
  4. Department of pathology, Shanghai Changzheng Hospital, Shanghai, China

Correspondence to:

Shu-han Sun, Department of Medical Genetics, Institute of Genetics, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. Tel./Fax: +86 021 8187 1055; E-mail: shsun@vip.sina.com

Received 5 May 2009; Accepted 2 July 2009

We here report that miR-17-92 cluster is a novel target for p53-mediated transcriptional repression under hypoxia. We found the expression levels of miR-17-92 cluster were reduced in hypoxia-treated cells containing wild-type p53, but were unchanged in hypoxia-treated p53-deficient cells. The repression of miR-17-92 cluster under hypoxia is independent of c-Myc. Luciferase reporter assays mapped the region responding to p53-mediated repression to a p53-binding site in the proximal region of the miR-17-92 promoter. Chromatin immunoprecipitation (ChIP), Re-ChIP and gel retardation assays revealed that the binding sites for p53- and the TATA-binding protein (TBP) overlap within the miR-17-92 promoter; these proteins were found to compete for binding. Finally, we show that pri-miR-17-92 expression correlated well with p53 status in colorectal carcinomas. Over-express miR-17-92 cluster markedly inhibits hypoxia-induced apoptosis, whereas blocked miR-17-5p and miR-20a sensitize the cells to hypoxia-induced apoptosis. These data indicated that p53-mediated repression of miR-17-92 expression likely has an important function in hypoxia-induced apoptosis, and thus further our understanding of the tumour suppressive function of p53.

  • Keywords:

    • apoptosis,
    • hypoxia,
    • microRNA 17-92 cluster,
    • p53,
    • transcriptional repression