Maintenance of the Undifferentiated State in Myogenic Progenitor Cells by TGFβ Signaling is Smad Independent and Requires MEK Activation

International Journal of Molecular Sciences

卷:21

Tetsuaki Miyake¹  Arif Aziz¹  John C. McDermott¹ 

[1] Department of Biology, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada;

关键词: tgfβ;    mek;    muscle;    differentiation;   

DOI  :  10.3390/ijms21031057

来源: DOAJ

【 摘 要 】

Transforming growth factor β (TGFβ) is a pluripotent cytokine and regulates a myriad of biological processes. It has been established that TGFβ potently inhibits skeletal muscle differentiation; however, the molecular mechanism is not clearly defined. Previously, we reported that inhibition of the TGFβ canonical pathway by an inhibitory Smad, Smad7, does not reverse this effect on differentiation, suggesting that activation of receptor Smads (R-Smads) by TGFβ is not responsible for repression of myogenesis. In addition, pharmacological blockade of Smad3 activation by TGFβ did not reverse TGFβ’s inhibitory effect on myogenesis. In considering other pathways, we observed that TGFβ potently activates MEK/ERK, and a pharmacological inhibitor of MEK reversed TGFβ’s inhibitory effect on myogenesis, as indicated by a myogenin promoter-reporter gene, sarcomeric myosin heavy chain accumulation, and phenotypic myotube formation. Furthermore, we found that c-Jun, a known potent repressor of myogenesis, which is coincidently also a down-stream target of MEK/ERK signaling, was phosphorylated and accumulates in the nucleus in response to TGFβ activation. Taken together, these observations support a model in which TGFβ activates a MEK/ERK/c-Jun pathway to repress skeletal myogenesis, maintaining the pluripotent undifferentiated state in myogenic progenitors.

【 授权许可】

Unknown