Tubaro Claudia, Arcuri Cataldo, Giambanco Ileana, Donato Rosario
Department of Experimental Medicine and Biochemical Sciences and Istituto Interuniversitario di Miologia, University of Perugia, Via del Glochetto, 06122 Perugia, Italy.
Biochim Biophys Acta. 2011 May;1813(5):1092-104. doi: 10.1016/j.bbamcr.2010.11.015. Epub 2010 Dec 2.
S100B protein activates IKKβ/NF-κB within myoblasts, thereby inhibiting the expression of MyoD and the MyoD-downstream effectors, myogenin and p21(WAF1), and myoblast differentiation. Herein we show that myoblasts downregulate S100B expression once transferred from proliferation medium to differentiation medium via a p38 MAPK-driven transcriptional mechanism as well as a post-translational, proteasome-dependent mechanism, and that myoblasts that have not been committed to differentiation resume expressing S100B once transferred back to proliferation medium. Likewise, myoblasts downregulate S100B expression once transferred to quiescence medium, and interference with S100B downregulation as obtained by stable overexpression of the protein results in reduced acquisition of quiescence and a faster proliferation upon transfer of the cells from quiescence medium to proliferation medium, compared to controls. These latter effects are dependent on S100B-induced activation of JNK. Moreover, S100B reduces myoblast apoptosis in an MEK-ERK1/2, Akt, JNK, and NF-κB-dependent manner. However, myogenin(+) myoblasts (i.e., myocytes) and myotubes abundantly express S100B likely induced by myogenin. Our results suggest that (1) a timely repression of S100B expression is required for efficient myogenic differentiation; (2) S100B plays an important role in the expansion of the activated (i.e., proliferating) myoblast population; (3) under conditions associated with enhanced expression of S100B, the transition from proliferation to quiescence and from quiescence to proliferation might be altered; and (4) S100B exerts different regulatory effects in myoblasts and myocytes/myotubes/myofibers. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
S100B蛋白可激活成肌细胞内的IKKβ/NF-κB，从而抑制MyoD及其下游效应分子肌细胞生成素和p21（WAF1）的表达，以及成肌细胞分化。在此我们发现，成肌细胞一旦从增殖培养基转移至分化培养基，便会通过p38丝裂原活化蛋白激酶驱动的转录机制以及翻译后、蛋白酶体依赖性机制下调S100B的表达，且未定向分化的成肌细胞一旦转回增殖培养基便会恢复S100B的表达。同样，成肌细胞一旦转移至静止培养基便会下调S100B的表达，与对照组相比，通过稳定过表达该蛋白来干扰S100B下调，会导致细胞从静止培养基转移至增殖培养基后静止状态的获得减少且增殖加快。这些后期效应依赖于S100B诱导的JNK激活。此外，S100B以MEK-ERK1/2、Akt、JNK和NF-κB依赖性方式减少成肌细胞凋亡。然而，肌细胞生成素阳性的成肌细胞（即肌细胞）和肌管大量表达可能由肌细胞生成素诱导的S100B。我们的结果表明：（1）高效的肌源性分化需要及时抑制S100B的表达；（2）S100B在活化（即增殖）的成肌细胞群体扩增中起重要作用；（3）在与S100B表达增强相关的条件下，从增殖到静止以及从静止到增殖的转变可能会改变；（4）S100B在成肌细胞和肌细胞/肌管/肌纤维中发挥不同的调节作用。本文是名为：第11届欧洲钙研讨会的特刊的一部分。
