Kataoka Yoshihisa, Matsumura Itaru, Ezoe Sachiko, Nakata Soichi, Takigawa Eri, Sato Yusuke, Kawasaki Akira, Yokota Takashi, Nakajima Koichi, Felsani Armando, Kanakura Yuzuru
Department of Hematology/Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.
J Biol Chem. 2003 Nov 7;278(45):44178-87. doi: 10.1074/jbc.M304884200. Epub 2003 Aug 28.
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.
成肌细胞的发育受多种生长因子以及内在的肌肉特异性转录因子调控。在本研究中，我们利用C2C12细胞，从细胞周期调控以及与MyoD的相互作用方面分析了STAT3在成肌细胞生长和分化中的作用。在此我们发现，STAT3抑制低血清或MyoD诱导的成肌分化的效率与Ras/丝裂原活化蛋白激酶级联反应相当。关于这一机制，我们发现STAT3不仅通过诱导c-myc促进细胞周期进程，还通过直接相互作用抑制MyoD活性。STAT3不仅抑制MyoD的DNA结合活性，还抑制其转录活性。然而，补充p300/CBP和PCAF可恢复被抑制的转录活性，这表明STAT3可能使MyoD失去这些转录辅因子。此外，我们发现MyoD抑制STAT3的DNA结合活性，从而抑制Ba/F3细胞中STAT3依赖的细胞生长和存活。这些结果表明，肌肉细胞的发育受细胞因子信号和内在转录因子协同作用的调控。
