TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation
TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation
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DOI：
10.1096/fj.13-228528
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发表时间：
2013-11-01
期刊：
影响因子：
4.8
通讯作者：
Bruni, Paola
中科院分区：
文献类型：
--
作者：
Cencetti, Francesca;Bernacchioni, Caterina;Bruni, Paola
鉴于其多种有害作用，转化生长因子1（TGF 1）被认为是骨骼肌修复的关键负调节因子。由TGF 1驱动的骨骼肌前体细胞凋亡有助于细胞因子在组织修复中发挥的负面作用，尽管潜在的分子机制仍然是难以捉摸的。在此，我们报道了一种新的信号通路的鉴定，该通路依赖于Rho激酶-2刺激，随后SMAD依赖性S1 P（4）上调和通过鞘氨醇激酶（SK）-2反式激活，其解释了TGF 1诱导的培养成肌细胞凋亡。TGF-1诱导的caspase-3和多聚ADP核糖基转移酶切割的激活使S1 P（4）特异性基因沉默减少了近50%。此外，选择性S1 P（4）拮抗剂CYM 50358也降低了TGF 1的促凋亡作用。通过采用药理学和分子生物学方法，也证明了SK 2和ROCK 2参与TGF 1凋亡作用的传递。这些结果强化了SK/S1 P轴在骨骼肌细胞中的TGF 1作用模式中起基本作用的概念，并且通过揭示TGF 1发挥其有害作用的新机制，确定了原则上可能有益于治疗几种骨骼肌病症或衰老依赖性肌肉萎缩的新分子靶点。Bernacchioni，C.，托内利，F.，Roberts，E.，多纳蒂角，Bruni，P. TGF 1通过一种涉及Rho激酶-2激活上游的S1 P（4）反式激活的新型信号通路引起成肌细胞凋亡反应。
In view of its multiple detrimental effects, transforming growth factor 1 (TGF1) is recognized as critical negative regulator of skeletal muscle repair. Apoptosis of skeletal muscle precursor cells driven by TGF1 contributes to the negative role exerted by the cytokine in tissue repair, although the underlying molecular mechanisms are still elusive. Herein we report the identification of a new signaling pathway, relying on Rho kinase-2 stimulation, subsequent to SMAD-dependent S1P(4) up-regulation and transactivation via sphingosine kinase (SK)-2, that accounts for TGF1-induced apoptosis in cultured myoblasts. S1P(4)-specific gene silencing reduced by almost 50% activation of caspase-3 and poly-ADP ribosyl transferase cleavage elicited by TGF1. Moreover, the selective S1P(4) antagonist CYM50358 also reduced the TGF1 proapoptotic effects. By employing pharmacological and molecular biological approaches, the involvement of SK2 and ROCK2 in the transmission of the TGF1 apoptotic action was also demonstrated. These results reinforce the notion that the SK/S1P axis plays a fundamental role in TGF1 mode of action in skeletal muscle cells and, by disclosing a novel mechanism by which TGF1 exerts its harmful action, pinpoint new molecular targets that in principle could be beneficial in the treatment of several skeletal muscle disorders or aging-dependent muscle atrophy.Cencetti, F., Bernacchioni, C., Tonelli, F., Roberts, E., Donati, C., Bruni, P. TGF1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P(4) transactivation upstream of Rho-kinase-2 activation.