Roles of mono-ubiquitinated Smad4 in the formation of Smad transcriptional complexes.
Roles of mono-ubiquitinated Smad4 in the formation of Smad transcriptional complexes.
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DOI：
10.1016/j.bbrc.2008.08.143
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发表时间：
2008-11
影响因子：
3.1
通讯作者：
Bei Wang;Hiroyuki Suzuki;Mitsuyasu Kato
中科院分区：
文献类型：
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作者：
Bei Wang;Hiroyuki Suzuki;Mitsuyasu Kato
TGF-β 通过 I 型受体磷酸化激活受体调节的 Smad (R-Smad)。激活的 R-Smad 与 Smad4 结合，该复合物易位到细胞核中，并通过与包括 p300 在内的共激活因子结合刺激靶基因的转录。然而，目前尚不清楚激活的 Smad 复合物是如何从靶基因上去除的。在这项研究中，我们发现 TGF-β 增强了 Smad4 的单泛素化。 Smad4 单泛素化由 p300 促进，并由 c-Ski 共阻遏物抑制。在存在组成型活性 TGF-β I 型受体的情况下，Smad4 单泛素化破坏了与 Smad2 的相互作用。此外，在 DNA 结合 Smad 复合物中没有发现单泛素化的 Smad4。 Smad4-泛素融合蛋白模拟单泛素化的 Smad4，增强了细胞质的定位。这些结果表明 Smad4 的单泛素化发生在转录激活复合物中，并促进 Smad 复合物在靶基因处的周转。
TGF-β activates receptor-regulated Smad (R-Smad) through phosphorylation by type I receptors. Activated R-Smad binds to Smad4 and the complex translocates into the nucleus and stimulates the transcription of target genes through association with co-activators including p300. It is not clear, however, how activated Smad complexes are removed from target genes. In this study, we show that TGF-β enhances the mono-ubiquitination of Smad4. Smad4 mono-ubiquitination was promoted by p300 and suppressed by the c-Ski co-repressor. Smad4 mono-ubiquitination disrupted the interaction with Smad2 in the presence of constitutively active TGF-β type I receptor. Furthermore, mono-ubiquitinated Smad4 was not found in DNA-binding Smad complexes. A Smad4-Ubiquitin fusion protein, which mimics mono-ubiquitinated Smad4, enhanced localization to the cytoplasm. These results suggest that mono-ubiquitination of Smad4 occurs in the transcriptional activator complex and facilitates the turnover of Smad complexes at target genes.