Ankyrin Repeat Domain Protein 2 and Inhibitor of DNA Binding 3 Cooperatively Inhibit Myoblast Differentiation by Physical Interaction*
Ankyrin Repeat Domain Protein 2 and Inhibitor of DNA Binding 3 Cooperatively Inhibit Myoblast Differentiation by Physical Interaction*
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DOI：
10.1074/jbc.m112.434423
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发表时间：
2013-07
期刊：
影响因子：
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通讯作者：
Junaith S Mohamed;Michael A. Lopez;G. Cox;A. Boriek
中科院分区：
文献类型：
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作者：
Junaith S Mohamed;Michael A. Lopez;G. Cox;A. Boriek
背景：营养不良的骨骼肌过表达强直蛋白重复结构域蛋白2(ANKRD2)，抑制成肌细胞分化。结果：MDM小鼠骨骼肌过表达ANKRD2和DNA结合抑制因子3(ID3)蛋白，通过物理作用协同抑制成肌细胞分化。结论：SREBP-1/ANKRD2/ID3通路的激活至少部分损伤了MDM小鼠骨骼肌的发育。意义：我们提供的证据揭示了ANKRD2表达抑制成肌细胞分化的新机制。Ankyrin Repeat结构域蛋白2(ANKRD2)在肌原诱导过程中从胞核转位到胞浆。ANKRD2过表达抑制C2C12成肌细胞分化。然而，ANKRD2抑制成肌细胞分化的机制尚不清楚。我们证明，MDM(肌营养不良伴肌炎)小鼠(PMBmdm)的原代成肌细胞过表达ANKRD2和ID3(DNA结合抑制物3)蛋白，并且不能在成肌诱导后分化为肌管。尽管抑制ANKRD2或ID3诱导MDM小鼠成肌细胞分化，但ANKRD2的过度表达和ID3的抑制或反之亦然，不足以抑制WT小鼠的成肌细胞分化。我们发现ANKRD2和ID3通过物理作用协同抑制成肌细胞分化。有趣的是，虽然MyoD激活了野生型小鼠骨骼肌中的Ankrd2启动子，但SREBP-1(固醇调节元件结合蛋白-1)在MDM小鼠的骨骼肌中激活了相同的启动子，提示Ankrd2的差异调控。总之，我们发现了SREBP-1/ANKRD2/ID3激活抑制成肌细胞分化的新途径，我们认为这一途径是骨骼肌发育计划的关键决定因素。
Background: Dystrophic skeletal muscles overexpress ankyrin repeat domain protein 2 (ANKRD2), which inhibits myoblast differentiation. Results: Skeletal muscles of the mdm mouse overexpress ANKRD2 and inhibitor of DNA binding 3 (ID3) proteins, which cooperatively inhibit myoblast differentiation by physical interaction. Conclusion: Activation of SREBP-1/ANKRD2/ID3 pathway impairs, at least in part, skeletal muscle development in mdm mice. Significance: We provide evidence revealing a novel mechanism by which expression of ANKRD2 inhibits myoblast differentiation. Ankyrin repeat domain protein 2 (ANKRD2) translocates from the nucleus to the cytoplasm upon myogenic induction. Overexpression of ANKRD2 inhibits C2C12 myoblast differentiation. However, the mechanism by which ANKRD2 inhibits myoblast differentiation is unknown. We demonstrate that the primary myoblasts of mdm (muscular dystrophy with myositis) mice (pMBmdm) overexpress ANKRD2 and ID3 (inhibitor of DNA binding 3) proteins and are unable to differentiate into myotubes upon myogenic induction. Although suppression of either ANKRD2 or ID3 induces myoblast differentiation in mdm mice, overexpression of ANKRD2 and inhibition of ID3 or vice versa is insufficient to inhibit myoblast differentiation in WT mice. We identified that ANKRD2 and ID3 cooperatively inhibit myoblast differentiation by physical interaction. Interestingly, although MyoD activates the Ankrd2 promoter in the skeletal muscles of wild-type mice, SREBP-1 (sterol regulatory element binding protein-1) activates the same promoter in the skeletal muscles of mdm mice, suggesting the differential regulation of Ankrd2. Overall, we uncovered a novel pathway in which SREBP-1/ANKRD2/ID3 activation inhibits myoblast differentiation, and we propose that this pathway acts as a critical determinant of the skeletal muscle developmental program.