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J. Biol. Chem., Vol. 282, Issue 4, 2135-2143, January 26, 2007
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An E2F/miR-20a Autoregulatory Feedback Loop*
11
¶234
From the
Département de Biochimie, Institut de Recherche en Immunologie et Cancer, ¶Département d'Informatique et Recherche Opérationnelle, Université de Montréal, Montréal, Quebec H3C 3J7, Canada
The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1–3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17–92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17–92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3'-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17–92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17–92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17–92 cluster. Altogether, these results suggest that the autoregulation between E2F1–3 and miR-20a is important for preventing an abnormal accumulation of E2F1–3 and may play a role in the regulation of cellular proliferation and apoptosis.
Received for publication, September 19, 2006 , and in revised form, November 24, 2006.
* This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (to F. M., G. F., and P. C.) and by a grant from the Cancer Research Society of Canada (to P. C.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental data and supplemental Fig. 1 and Tables 1 and 2.
1 These authors contributed equally to this work.
2 Supported by a Canadian Institutes of Health Research (CIHR) fellowship.
3 Supported by a CIHR New Investigator fellowship. To whom correspondence may be addressed: Dépt. de Biochimie, Université de Montréal, 2900 Edouard-Montpetit, Montréal, Quebec H3C 3J7, Canada. Tel.: 514-343-7571; Fax: 514-343-2210; E-mail: g.ferbeyre{at}umontreal.ca. 4 Supported by a fellowship from the Fond de Recherche sur la Nature et les Technologies du Québec (NATEQ). To whom correspondence may be addressed: Dépt. de Biochimie, Université de Montréal, 2900 Edouard-Montpetit, Montréal, Quebec H3C 3J7, Canada. Tel.: 514-343-5684; Fax: 514-343-2210; E-mail: p.chartrand{at}umontreal.ca.
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