Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling.
Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling.
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DOI：
10.1186/2044-5040-3-7
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发表时间：
2013-04-02
期刊：
影响因子：
4.9
通讯作者：
McDermott JC
中科院分区：
文献类型：
--
作者：
Dionyssiou MG;Salma J;Bevzyuk M;Wales S;Zakharyan L;McDermott JC
KRüppel-like factor6(KLF6)是最近发现的与神经细胞存活相关的MEF2D靶基因。此外，KLF6和转化生长因子β已经被证明在非肌源性细胞类型中相互调节对方的表达。由于MEF2D和转化生长因子β也在骨骼肌发生中发挥关键作用，我们想要确定KLF6是否在肌肉发生的背景下发挥作用。在细胞培养中使用标准的细胞和分子技术分析KLF6蛋白表达水平和启动子活性。我们发现KLF6和MEF2D共同定位于单核而不是多核肌源性细胞的细胞核中，并且MEF2顺式元件是KLF6启动子区域的关键组成部分。此外，转化生长因子β可显著提高KLF6蛋白水平，这种作用可被Smad3的药理抑制作用所抑制。有趣的是，药物抑制mek/erk(1/2)信号导致转化生长因子β处理的成肌细胞中的分化程序重新激活，而这通常被转化生长因子β处理所抑制。相反，抑制MK/ERK(1/2)对转化生长因子β诱导的KLF6表达没有影响，而抑制Smad3则抵消了这一作用，共同支持转化生长因子β信号通路的两个可分离臂在肌源性细胞中的存在。小干扰RNA介导的KLF6缺失功能分析结果显示，KLF6缺失细胞的成肌分化增强，而转化生长因子β对成肌细胞增殖的刺激作用减弱。总而言之，这些数据表明KLF6参与了成肌细胞的增殖和存活，从而影响了我们对肌肉发育和各种肌肉病理的理解。
Krüppel-like factor 6 (KLF6) has been recently identified as a MEF2D target gene involved in neuronal cell survival. In addition, KLF6 and TGFβ have been shown to regulate each other’s expression in non-myogenic cell types. Since MEF2D and TGFβ also fulfill crucial roles in skeletal myogenesis, we wanted to identify whether KLF6 functions in a myogenic context. KLF6 protein expression levels and promoter activity were analyzed using standard cellular and molecular techniques in cell culture. We found that KLF6 and MEF2D are co-localized in the nuclei of mononucleated but not multinucleated myogenic cells and, that the MEF2 cis element is a key component of the KLF6 promoter region. In addition, TGFβ potently enhanced KLF6 protein levels and this effect was repressed by pharmacological inhibition of Smad3. Interestingly, pharmacological inhibition of MEK/ERK (1/2) signaling resulted in re-activation of the differentiation program in myoblasts treated with TGFβ, which is ordinarily repressed by TGFβ treatment. Conversely, MEK/ERK (1/2) inhibition had no effect on TGFβ-induced KLF6 expression whereas Smad3 inhibition negated this effect, together supporting the existence of two separable arms of TGFβ signaling in myogenic cells. Loss of function analysis using siRNA-mediated KLF6 depletion resulted in enhanced myogenic differentiation whereas TGFβ stimulation of myoblast proliferation was reduced in KLF6 depleted cells. Collectively these data implicate KLF6 in myoblast proliferation and survival in response to TGFβ with consequences for our understanding of muscle development and a variety of muscle pathologies.
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