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J. Biol. Chem., Vol. 283, Issue 24, 16545-16553, June 13, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/24/16545    most recent M709604200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, S. K. M. Articles by Yao, K.-M. Search for Related Content PubMed PubMed Citation Articles by Li, S. K. M. Articles by Yao, K.-M. Social Bookmarking                      What's this?

FoxM1c Counteracts Oxidative Stress-induced Senescence and Stimulates Bmi-1 Expression^*

Samuel K. M. Li, David K. Smith, Wai Ying Leung, Alice M. S. Cheung, Eric W. F. Lam, Goberdhan P. Dimri^¶, and Kwok-Ming Yao¹

From the Department of Biochemistry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China, ^¶Department of Medicine, Evanston Northwestern Healthcare Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60201, and Cancer Research-United Kingdom Laboratories, Department of Oncology, Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom

The Forkhead box transcription factor FoxM1 is expressed in proliferating cells. When it was depleted in mice and cell lines, cell cycle defects and chromosomal instability resulted. Premature senescence was observed in embryonic fibroblasts derived from FoxM1 knock-out mice, but the underlying cause has remained unclear. To investigate whether FoxM1 can protect cells against stress-induced premature senescence, we established NIH3T3 lines with doxycycline-inducible overexpression of FoxM1c. Treatment of these lines with sublethal doses (20 and 100 µM) of H₂O₂ induced senescence with senescence-associated β-galactosidase expression and elevated levels of p53 and p21. Induction of FoxM1c expression markedly suppressed senescence and expression of p53 and p21. Consistent with down-regulation of the p19^Arf-p53 pathway, p19^Arf levels decreased while expression of the Polycomb group protein Bmi-1 was induced. That Bmi-1 is a downstream target of FoxM1c was further supported by the dose-dependent induction of Bmi-1 by FoxM1c at both the protein and mRNA levels, and FoxM1 and Bmi-1 reached maximal levels in cells at the G₂/M phase. Depletion of FoxM1 by RNA interference decreased Bmi-1 expression. Using Bmi-1 promoter reporters with wild-type and mutated c-Myc binding sites and short hairpin RNAs targeting c-Myc, we further demonstrated that FoxM1c activated Bmi-1 expression via c-Myc, which was recently reported to be regulated by FoxM1c. Our results reveal a functional link between FoxM1c, c-Myc, and Bmi-1, which are major regulators of tumorigenesis. This link has important implications for the regulation of cell proliferation and senescence by FoxM1 and Bmi-1.

Received for publication, November 26, 2007 , and in revised form, April 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 CA094150 (to G. P. D.). This work was also supported by Research Grants Council Grant 7650/05M and a Hong Kong University Small Project Fund (to K. M. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, LKS Faculty of Medicine, University of Hong Kong, 3/F Laboratory Block, LKS Faculty of Medicine Bldg., 21 Sassoon Rd., Pokfulam, Hong Kong SAR, China. Tel.: 852-2819-9275; Fax: 852-2855-1254; E-mail: kmyao{at}hkusua.hku.hk.

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