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Coordinated Regulation of Cell Cycle Transcripts by p53-Inducible microRNAs, miR-192 and miR-215

Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington

Requests for reprints: Sara A. Georges, Rosetta Inpharmatics LLC, 401 Terry Avenue North, Seattle, WA 98109. E-mail: sara_georges{at}merck.com or B. Nelson Chau, Regulus Therapeutics, 1896 Rutherford Road, Carlsbad, CA 92008. Phone: 760-268-6819; Fax: 760-268-6802; E-mail: NChau{at}regulusrx.com.

Key Words: microRNA • cell cycle arrest • p53 • gene expression profiling • RNA interference

Cell cycle arrest in response to DNA damage is an important antitumorigenic mechanism. MicroRNAs (miRNAs) were recently shown to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G₁ arrest by down-regulating multiple cell cycle–related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs miR-192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest, suggesting that multiple miRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G₁ and G₂ checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215, and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors. [Cancer Res 2008;68(24):10105–12]

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