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首页> 外文期刊>The FASEB Journal >TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation.
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TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation.

机译：TGFβ1 通过一种新的信号通路诱导成肌细胞凋亡反应，该通路涉及 Rho-激酶-2 激活上游的 S1P4 反式激活。

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摘要

In view of its multiple detrimental effects, transforming growth factor β1 (TGFβ1) is recognized as critical negative regulator of skeletal muscle repair. Apoptosis of skeletal muscle precursor cells driven by TGFβ1 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 S1P4 up-regulation and transactivation via sphingosine kinase (SK)-2, that accounts for TGFβ1-induced apoptosis in cultured myoblasts. S1P4-specific gene silencing reduced by almost 50 activation of caspase-3 and poly-ADP ribosyl transferase cleavage elicited by TGFβ1. Moreover, the selective S1P4 antagonist CYM50358 also reduced the TGFβ1 proapoptotic effects. By employing pharmacological and molecular biological approaches, the involvement of SK2 and ROCK2 in the transmission of the TGFβ1 apoptotic action was also demonstrated. These results reinforce the notion that the SK/S1P axis plays a fundamental role in TGFβ1 mode of action in skeletal muscle cells and, by disclosing a novel mechanism by which TGFβ1 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. TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation.
机译：鉴于其多种有害影响，转化生长因子 β1 （TGFβ1） 被认为是骨骼肌修复的关键负调节因子。TGFβ1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负面作用，尽管潜在的分子机制仍然难以捉摸。在此，我们报告了一种新的信号通路的鉴定，依赖于 Rho 激酶-2 刺激，继 SMAD 依赖性 S1P4 上调和通过鞘氨醇激酶 （SK）-2 反式激活之后，这解释了 TGFβ1 诱导的培养成肌细胞中的细胞凋亡。S1P4 特异性基因沉默减少了近 50% 的 TGFβ1 引发的 caspase-3 和 poly-ADP 核糖基转移酶切割的激活。此外，选择性的 S1P4 拮抗剂CYM50358也降低了 TGFβ1 的促凋亡作用。通过采用药理学和分子生物学方法，还证明了 SK2 和 ROCK2 参与 TGFβ1 凋亡作用的传递。这些结果强化了SK / S1P轴在骨骼肌细胞中TGFβ1作用模式中起基本作用的概念，并且通过揭示TGFβ1发挥其有害作用的新机制，确定了新的分子靶点，原则上可能有益于治疗几种骨骼肌疾病或衰老依赖性肌肉萎缩。 F.， Bernacchioni， C.， Tonelli， F.， Roberts， E.， Donati， C.， Bruni， P.TGFβ1 通过一种新的信号通路诱导成肌细胞凋亡反应，该通路涉及 Rho-激酶-2 激活上游的 S1P4 反式激活。

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