Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation

Koshiro Monzen, Yukio Hiroi, Sumiyo Kudoh, Hiroshi Akazawa, Toru Oka, Eiki Takimoto, Doubun Hayashi, Toru Hosoda, Masahiro Kawabata, Kohei Miyazono, Shunsuke Ishii, Yoshio Yazaki, Ryozo Nagai, Issei Komuro

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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-β 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 βMHC 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.

Original languageEnglish (US)
Pages (from-to)687-698
Number of pages12
JournalJournal of Cell Biology
Issue number4
StatePublished - May 14 2001
Externally publishedYes


  • ATF-2
  • Bone morphogenetic protein
  • Cardiomyocyte differentiation
  • P19CL6
  • Smad

ASJC Scopus subject areas

  • Cell Biology


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