SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling
SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling
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DOI：
10.1038/ncb753
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发表时间：
2002-03-01
影响因子：
21.3
通讯作者：
Duyster, J
中科院分区：
文献类型：
--
作者：
Bai, RY;Koester, C;Duyster, J
转化生长因子β (tgfβ)超家族蛋白调节多种细胞反应，包括细胞生长和分化。在tgfβ刺激后，受体相关的Smads被磷酸化，并与共同介质Smad4形成复合物。在这里，我们报道了SMIF的克隆，SMIF是一种普遍表达的，与smad4相互作用的转录共激活因子。SMIF与Smad4形成tgf β /骨形态发生蛋白4 （BMP4）诱导复合物，但不与其他Smads形成，并以tgf β /BMP4诱导和Smad4依赖的方式易位到细胞核。SMIF具有很强的内在tgfβ诱导的转录活性，在哺乳动物细胞中依赖于Smad4，需要p300/CBP。在转录分析中，Smad4的一个点突变破坏了与SMIF的结合，并削弱了其活性。野生型SMIF过表达增强了tgf β /BMP调控基因的表达，而显性阴性SMIF突变体抑制了表达。此外，显性阴性SMIF能够阻断tgf - β诱导的生长抑制。在一种以斑马鱼SMIF为靶点的morpholino反义寡核苷酸敲低方法中，在斑马鱼胚胎中观察到严重但明显的表型缺陷。因此，我们提出SMIF是tgf - β信号传导的关键激活因子。
Proteins of the transforming growth factor beta (TGFbeta) superfamily regulate diverse cellular responses, including cell growth and differentiation. After TGFbeta stimulation, receptor-associated Smads are phosphorylated and form a complex with the common mediator Smad4. Here, we report the cloning of SMIF, a ubiquitously expressed, Smad4-interacting transcriptional co-activator. SMIF forms a TGFbeta/bone morphogenetic protein 4 (BMP4)-inducible complex with Smad4, but not with others Smads, and translocates to the nucleus in a TGFbeta/BMP4-inducible and Smad4-dependent manner. SMIF possesses strong intrinsic TGFbeta-inducible transcriptional activity, which is dependent on Smad4 in mammalian cells and requires p300/CBP. A point mutation in Smad4 abolished binding to SMIF and impaired its activity in transcriptional assays. Overexpression of wild-type SMIF enhanced expression of TGFbeta/BMP regulated genes, whereas a dominant-negative SMIF mutant suppressed expression. Furthermore, dominant-negative SMIF is able to block TGFbeta-induced growth inhibition. In a knockdown approach with morpholinoantisense oligonucleotides targeting zebrafish SMIF, severe but distinct phenotypic defects were observed in zebrafish embryos. Thus, we propose that SMIF is a crucial activator of TGFbeta signalling.