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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation of Fli1 at Threonine 312 by Protein Kinase C δ Promotes Its Interaction with p300/CREB-Binding Protein-Associated Factor and Subsequent Acetylation in Response to Transforming Growth Factor β
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Phosphorylation of Fli1 at Threonine 312 by Protein Kinase C δ Promotes Its Interaction with p300/CREB-Binding Protein-Associated Factor and Subsequent Acetylation in Response to Transforming Growth Factor β

机译：蛋白激酶Cδ在苏氨酸312上对Fli1的磷酸化促进了其与p300 / CREB结合蛋白相关因子的相互作用以及随后对转化生长因子β的乙酰化作用

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Previous studies have shown that transforming growth factor β (TGF-β)-induced collagen gene expression involves acetylation-dependent dissociation from the human α2(I) collagen (COL1A2) promoter of the transcriptional repressor Fli1. The goal of this study was to elucidate the regulatory steps preceding the acetylation of Fli1. We first showed that TGF-β induces Fli1 phosphorylation on a threonine residue(s). The major phosphorylation site was localized to threonine 312 located in the DNA binding domain of Fli1. Using several independent approaches, we demonstrated that Fli1 is directly phosphorylated by protein kinase C δ (PKC δ). Additional experiments showed that in response to TGF-β, PKC δ is recruited to the collagen promoter to phosphorylate Fli1 and that this step is a prerequisite for the subsequent interaction of Fli1 with p300/CREB-binding protein-associated factor (PCAF) and an acetylation event. The phosphorylation of endogenous Fli1 preceded its acetylation in response to TGF-β stimulation, and the blockade of PKC δ abrogated both the phosphorylation and acetylation of Fli1 in dermal fibroblasts. Promoter studies showed that a phosphorylation-deficient mutant of Fli1 exhibited an increased inhibitory effect on the COL1A2 gene, which could not be reversed by the forced expression of PCAF or PKC δ. These data strongly suggest that the phosphorylation-acetylation cascade triggered by PKC δ represents the primary mechanism whereby TGF-β regulates the transcriptional activity of Fli1 in the context of the collagen promoter.
机译：先前的研究表明，转化生长因子β（TGF-β）诱导的胶原蛋白基因表达涉及从转录阻遏物Fli1的人α2（I）胶原蛋白（COL1A2）启动子的乙酰化依赖性解离。这项研究的目的是阐明Fli1乙酰化之前的调控步骤。我们首先表明，TGF-β诱导苏氨酸残基上的Fli1磷酸化。主要的磷酸化位点定位于位于Fli1的DNA结合域中的苏氨酸312。使用几种独立的方法，我们证明了Fli1被蛋白激酶Cδ（PKCδ）直接磷酸化。其他实验表明，响应TGF-β，PKCδ被募集到胶原蛋白启动子上以磷酸化Fli1，并且该步骤是Fli1与p300 / CREB结合蛋白相关因子（PCAF）和蛋白相互作用的后续前提。乙酰化事件。响应TGF-β刺激，内源性Fli1的磷酸化先于其乙酰化，并且PKCδ的阻断消除了皮肤成纤维细胞中Fli1的磷酸化和乙酰化。启动子研究表明，Fli1的磷酸化缺陷突变体对COL1A2基因的抑制作用增强，而PCAF或PKCδ的强制表达不能逆转该抑制作用。这些数据强烈表明由PKCδ触发的磷酸化-乙酰化级联反应是TGF-β调节胶原启动子中Fli1转录活性的主要机制。

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