Oligodendrocyte Transcription Factor 1 (Olig1) Is a Smad Cofactor Involved in Cell Motility Induced by Transforming Growth Factor-β
Oligodendrocyte Transcription Factor 1 (Olig1) Is a Smad Cofactor Involved in Cell Motility Induced by Transforming Growth Factor-β
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DOI：
10.1074/jbc.m113.480996
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发表时间：
2013-06-28
影响因子：
4.8
通讯作者：
Miyazawa, Keiji
中科院分区：
文献类型：
--
作者：
Motizuki, Mitsuyoshi;Isogaya, Kazunobu;Miyazawa, Keiji
转化生长因子(TGF)- β通过在靶细胞中引发各种细胞反应，在胚胎发育和成体组织稳态中发挥重要作用。tgf - β信号主要通过受体激活的Smad蛋白介导，Smad蛋白与其他dna结合转录因子（Smad辅因子）协同调节靶基因的表达。在这项研究中，我们发现基本螺旋-环-螺旋转录因子Olig1是参与tgf - β诱导的细胞运动的Smad辅助因子。在腔室迁移和伤口愈合试验中，敲低Olig1可减弱tgf - β诱导的细胞运动。相反，Olig1敲低对骨形态发生蛋白诱导的细胞运动、tgf - β诱导的细胞停滞或上皮-间质转化没有影响。此外，我们观察到Smad2/3与Olig1的合作受到肽基脯氨酸顺式/反式异构酶Pin1的调节。在敲低Pin1后，tgf - β诱导的细胞运动、Olig1调控基因的诱导以及Smad2/3与Olig1之间的物理相互作用都被抑制，这表明Smad信号传导的一种新的调节模式。我们还发现Olig1与Smad3的L3环相互作用。利用Smad3 L3环对应的合成肽，我们成功地选择性抑制了tgf - β诱导的细胞运动。这些发现可能导致对tgf - β诱导的细胞反应的选择性调节的新策略。
Transforming growth factor (TGF)-beta plays crucial roles in embryonic development and adult tissue homeostasis by eliciting various cellular responses in target cells. TGF-beta signaling is principally mediated through receptor-activated Smad proteins, which regulate expression of target genes in cooperation with other DNA-binding transcription factors (Smad cofactors). In this study, we found that the basic helix-loop-helix transcription factor Olig1 is a Smad cofactor involved in TGF-beta-induced cell motility. Knockdown of Olig1 attenuated TGF-beta-induced cell motility in chamber migration and wound healing assays. In contrast, Olig1 knockdown had no effect on bone morphogenetic protein-induced cell motility, TGF-beta-induced cytostasis, or epithelial-mesenchymal transition. Furthermore, we observed that cooperation of Smad2/3 with Olig1 is regulated by a peptidyl-prolyl cis/trans-isomerase, Pin1. TGF-beta-induced cell motility, induction of Olig1-regulated genes, and physical interaction between Smad2/3 and Olig1 were all inhibited after knockdown of Pin1, indicating a novel mode of regulation of Smad signaling. We also found that Olig1 interacts with the L3 loop of Smad3. Using a synthetic peptide corresponding to the L3 loop of Smad3, we succeeded in selectively inhibiting TGF-beta-induced cell motility. These findings may lead to a new strategy for selective regulation of TGF-beta-induced cellular responses.