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J. Biol. Chem., Vol. 283, Issue 26, 18158-18166, June 27, 2008

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MicroRNA miR-199a^* Regulates the MET Proto-oncogene and the Downstream Extracellular Signal-regulated Kinase 2 (ERK2)^*

Seonhoe Kim¹, Ui Jin Lee¹, Mi Na Kim¹, Eun-Ju Lee, Ji Young Kim, Mi Young Lee, Sorim Choung, Young Joo Kim, and Young-Chul Choi²

From the Gene2Drug Research Center, Bioneer Corporation, and National Genome Information Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 306-220, Republic of Korea

MicroRNAs (miRNAs) constitute a class of small noncoding RNAs that play important roles in a variety of biological processes including development, apoptosis, proliferation, and differentiation. Here we show that the expression of miR-199a and miR-199a^*(miR-199a/a^*), which are processed from the same precursor, is confined to fibroblast cells among cultured cell lines. The fibroblast-specific expression pattern correlated well with methylation patterns: gene loci on chromosome 1 and 19 were fully methylated in all examined cell lines but unmethylated in fibroblasts. Transfection of miR-199a and/or -199a^* mimetics into several cancer cell lines caused prominent apoptosis with miR-199a^* being more pro-apoptotic. The mechanism underlying apoptosis induced by miR-199a was caspase-dependent, whereas a caspase-independent pathway was involved in apoptosis induced by miR-199a^* in A549 cells. By employing microarray and immunoblotting analyses, we identified the MET proto-oncogene as a target of miR-199a^*. Studies with a luciferase reporter fused to the 3'-untranslated region of the MET gene demonstrated miR-199a^*-mediated down-regulation of luciferase activity through a binding site of miR-199a^*. Interestingly, extracellular signal-regulated kinase 2 (ERK2) was also down-regulated by miR-199a^*. Coordinated down-regulation of both MET and its downstream effector ERK2 by miR-199a^* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.

Received for publication, January 9, 2008 , and in revised form, May 2, 2008.

^* This work was supported in part by Next Generation New Technology Development Program Grant 10030036 from the Ministry of Commerce, Industry, and Energy in Korea (to Y.-C. 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 Figs. S1–S7 and Tables S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 49-3, Munpyeong-dong, Daedeok-gu, Daejeon, 306-220, Republic of Korea. Fax: 82-42-930-8600; E-mail: youcchoi{at}hanmail.net.

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