Reciprocal Inhibition between MyoD and STAT3 in the Regulation of Growth and Differentiation of Myoblasts

Yuzuru Kanakura,Sachiko Ezoe,Itaru Matsumura,Yoshihisa Kataoka,Soichi Nakata,Eri Takigawa,Armando Felsani,Koichi Nakajima,Akira Kawasaki,Takashi Yokota,Yusuke Sato

doi:10.1074/jbc.m304884200

Abstract

The development of myoblasts is regulated by various growth factors as well as by intrinsic muscle-specific transcriptional factors. In this study, we analyzed the roles for STAT3 in the growth and differentiation of myoblasts in terms of cell cycle regulation and interaction with MyoD using C2C12 cells. Here we found that STAT3 inhibited myogenic differentiation induced by low serum or MyoD as efficiently as the Ras/mitogen-activated protein kinase cascade. As for this mechanism, we found that STAT3 not only promoted cell cycle progression through the induction of c-myc but also inhibited MyoD activities through direct interaction. STAT3 inhibited not only DNA binding activities of MyoD but also its transcriptional activities. However, the inhibited transcriptional activities were restored by the supplement of p300/CBP and PCAF, suggesting that STAT3 might deprive MyoD of these transcriptional cofactors. In addition, we found that MyoD inhibited DNA binding activities of STAT3, thereby inhibiting STAT3-dependent cell growth and survival of Ba/F3 cells. These results suggest that the development of muscle cells is regulated by the coordination of cytokine signals and intrinsic transcription factors.

Highlights

The development of myoblasts is regulated by various growth factors as well as by intrinsic muscle-specific transcriptional factors
To examine the roles for STAT3, which can be activated by leukemia inhibitory factor (LIF), IL-6, insulin-like growth factor (IGF)-I, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), or basic fibroblast growth factor (bFGF), in myogenic differentiation under these culture systems, we introduced MyoD/ER and G-CSFR/gp130 that can activate STAT3 into C2 and C3; these clones were designated as C2/gp130/MyoD/ER and C3/gp130/MyoD/ER, respectively
As for myogenesis, the Ras/mitogen-activated protein kinase (MAPK) pathway activated by IGF-I, IGF-II, HGF, or bFGF was reported to participate in cell cycle progression (44 – 48), it was shown to mediate terminal differentiation in other papers [49, 50]

Summary

Introduction

The development of myoblasts is regulated by various growth factors as well as by intrinsic muscle-specific transcriptional factors. We found that STAT3 inhibits myogenic differentiation induced by low serum or MyoD as efficiently as the Ras/mitogen-activated protein kinase (MAPK) cascade.

Results

Conclusion