Basal Signalling Through Death Receptor 5 and Caspase 3 Activates p38 Kinase to Regulate Serum Response Factor (SRF)-Mediated MyoD Transcription.

Q2 Biochemistry, Genetics and Molecular Biology Journal of Molecular Signaling Pub Date : 2020-05-08 DOI:10.5334/1750-2187-14-1
Jason A Ross, Brianna Barrett, Victoria Bensimon, Girish Shukla, Crystal M Weyman
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Abstract

We have previously reported that stable expression of a dominant negative Death Receptor 5 (dnDR5) in skeletal myoblasts results in decreased basal caspase activity and decreased mRNA and protein expression of the muscle regulatory transcription factor MyoD in growth medium (GM), resulting in inhibited differentation when myoblasts are then cultured in differentiation media (DM). Further, this decreased level of MyoD mRNA was not a consequence of altered message stability, but rather correlated with decreased acetylation of histones in the distal regulatory region (DRR) of the MyoD extended promoter known to control MyoD transcription. As serum response factor (SRF) is the transcription factor known to be responsible for basal MyoD expression in GM, we compared the level of SRF binding to the non-canonical serum response element (SRE) within the DRR in parental and dnDR5 expressing myoblasts. Herein, we report that stable expression of dnDR5 resulted in decreased levels of serum response factor (SRF) binding to the CArG box in the SRE of the DRR. Total SRF expression levels were not affected, but phosphorylation indicative of SRF activation was impaired. This decreased SRF phosphorylation correlated with decreased phosphorylation-induced activation of p38 kinase. Moreover, the aforementioned signaling events affected by expression of dnDR5 could be appropriately recapitulated using either a pharmacological inhibitor of caspase 3 or p38 kinase. Thus, our results have established a signaling pathway from DR5 through caspases to p38 kinase activation, to SRF activation and the basal expression of MyoD.

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通过死亡受体 5 和 Caspase 3 发出的基础信号可激活 p38 激酶,从而调节血清反应因子 (SRF) 介导的 MyoD 转录。
我们以前曾报道过,在骨骼肌母细胞中稳定表达显性阴性死亡受体5(dnDR5)会导致生长培养基(GM)中的基础Caspase活性降低、肌肉调控转录因子MyoD的mRNA和蛋白表达量减少,从而抑制了肌母细胞在分化培养基(DM)中的分化。此外,MyoD mRNA水平的降低并不是信息稳定性改变的结果,而是与已知控制MyoD转录的MyoD扩展启动子远端调节区(DRR)组蛋白乙酰化的降低有关。由于血清反应因子(SRF)是已知在转基因中负责MyoD基础表达的转录因子,我们比较了亲代和表达dnDR5的肌母细胞中SRF与DRR内的非经典血清反应元件(SRE)的结合水平。在此,我们报告了稳定表达 dnDR5 会导致血清反应因子(SRF)与 DRR SRE 中 CArG 框的结合水平下降。SRF的总表达水平未受影响,但SRF活化的磷酸化却受到了影响。SRF 磷酸化的减少与磷酸化诱导的 p38 激酶活化的减少相关。此外,上述受dnDR5表达影响的信号转导事件可通过使用caspase 3或p38激酶的药理抑制剂适当地再现。因此,我们的研究结果建立了一条从DR5通过caspase到p38激酶激活,再到SRF激活和MyoD基础表达的信号通路。
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Journal of Molecular Signaling
Journal of Molecular Signaling Biochemistry, Genetics and Molecular Biology-Biochemistry
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期刊介绍: Journal of Molecular Signaling is an open access, peer-reviewed online journal that encompasses all aspects of molecular signaling. Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. Specifically, the research area of the journal is on the normal or aberrant molecular mechanisms involving receptors, G-proteins, kinases, phosphatases, and transcription factors in regulating cell proliferation, differentiation, apoptosis, and oncogenesis in mammalian cells. This area also covers the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological conditions.
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