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Published online 7 May 2001. doi:10.1083/jcb.153.4.687
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© The Rockefeller University Press, 0021-9525/2001/5/687/ $5.00
The Journal of Cell Biology, Volume 153, Number 4, May 14, 2001 687-698

Original Article

Smads, TAK1, and Their Common Target ATF-2 Play a Critical Role in Cardiomyocyte Differentiation

Koshiro Monzena, Yukio Hiroia, Sumiyo Kudoha, Hiroshi Akazawab, Toru Okaa, Eiki Takimotoa, Doubun Hayashia, Toru Hosodaa, Masahiro Kawabatac, Kohei Miyazonoc, Shunsuke Ishiid, Yoshio Yazakie, Ryozo Nagaia, and Issei Komurob
a Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan
b Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
c Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan
d The Laboratory of Molecular Genetics, Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Tsukuba, Ibaraki 305-0074, Japan
e International Medical Center of Japan, Tokyo 162-8655, Japan

Correspondence to: Issei Komuro, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel:81-43-226-2097 Fax:81-43-226-2557 E-mail:komuro-tky{at}umin.ac.jp.

We previously demonstrated that bone morphogenetic proteins (BMPs) induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1. Transcription factors Smads mediate transforming growth factor-ß signaling and the ATF/CREB family transcription factor ATF-2 has recently been shown to act as a common target of the Smad and the TAK1 pathways. We here examined the role of Smads and ATF-2 in cardiomyocyte differentiation of P19CL6, a clonal derivative of murine P19 cells. Although P19CL6 efficiently differentiates into cardiomyocytes when treated with dimethyl sulfoxide, P19CL6noggin, a P19CL6 cell line constitutively overexpressing the BMP antagonist noggin, did not differentiate into cardiomyocytes. Cooverexpression of Smad1, a ligand-specific Smad, and Smad4, a common Smad, restored the ability of P19CL6noggin to differentiate into cardiomyocytes, whereas stable overexpression of Smad6, an inhibitory Smad, completely blocked differentiation of P19CL6, suggesting that the Smad pathway is necessary for cardiomyocyte differentiation. ATF-2 stimulated the ßMHC promoter activity by the synergistic manner with Smad1/4 and TAK1 and promoted terminal cardiomyocyte differentiation of P19CL6noggin, whereas overexpression of the dominant negative form of ATF-2 reduced the promoter activities of several cardiac-specific genes and inhibited differentiation of P19CL6. These results suggest that Smads, TAK1, and their common target ATF-2 cooperatively play a critical role in cardiomyocyte differentiation.

Key Words: bone morphogenetic protein, Smad, ATF-2, cardiomyocyte differentiation, P19CL6


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