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(Circulation Research. 2002;91:382.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Regulation of Smooth Muscle Cell Differentiation by AT-Rich Interaction Domain Transcription Factors Mrf2 and Mrf2ß

Masafumi Watanabe, Matthew D. Layne, Chung-Ming Hsieh, Koji Maemura, Susan Gray, Mu-En Lee, Mukesh K. Jain

From the Cardiovascular (M.W., M.D.L., C.-M.H., K.M., S.G., M.-E.L., M.K.J.) and Pulmonary and Critical Care (M.D.L.) Divisions, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Mukesh K. Jain, MD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, TH1127, Boston, MA 02115. E-mail mjain{at}rics.bwh.harvard.edu

Despite the importance of vascular smooth muscle cells in the regulation of blood vessel function, the molecular mechanisms governing their development and differentiation remain poorly understood. Using an in vitro system whereby a pluripotent neural crest cell line (MONC-1) can be induced to differentiate into smooth muscle cells, we isolated a cDNA fragment that was robustly induced during this differentiation process. Sequence analysis revealed high homology to a partial cDNA termed modulator recognition factor 2 (Mrf2). Because the full-length cDNA has not been reported, we cloned the full-length Mrf2 cDNA by cDNA library screening and 5' rapid amplification of cDNA ends and identified two isoforms of Mrf2 ( [3.0 kb] and ß [3.7 kb]) that differ in the N-terminus but share the DNA-binding domain. Protein homology analysis suggests that Mrf2 is a member of the AT-rich interaction domain family of transcription factors, which are known to be critically involved in the regulation of development and cellular differentiation. Mrf2 and Mrf2ß are highly induced during in vitro differentiation of MONC-1 cells into smooth muscle cells, and Mrf2 is expressed in adult mouse cardiac and vascular tissues. To define the function of Mrf2, we overexpressed both isoforms in 3T3 fibroblast cells and observed an induction of smooth muscle marker genes, including smooth muscle -actin and smooth muscle 22. Furthermore, Mrf2 and Mrf2ß retarded cellular proliferation. These data implicate Mrf2 as a novel regulator of smooth muscle cell differentiation and proliferation.

Key Words: smooth muscle • differentiation • proliferation • transcription factors

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