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Transcriptional regulation of the target genes of transforming growth factor-β and it's abnormalities in disease.

转化生长因子-β靶基因的转录调控及其在疾病中的异常。

基本信息

批准号：
14570208
负责人：
KATO Mitsuyasu
金额：
$ 2.62万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570208/
关键词：
TGF-β Smad transcription c-myc WNT TCF-4 LEF-1 c-Ski TIE E2Fエレメント smad β-catemin TBE3エレメント

项目摘要

We have identified a TIE/E2F element that is critical for transcriptional regulation of c-myc in both serum-induced induction and TGF-β-induced suppression. Another element TBE3 that is activated by WNT signaling is also identified in the transcriptional regulatory region of c-myc. TGF-β-activated Smad3 binds a TIE/E2F element and dissociates p300 from E2F-4. On TBE3, TCF-4 releases β-catenin when binds Smad3. However, LEF-1 can bind both β-catenin and Smad3 at the same time. Therefore, transcriptional activity of c-myc activated by β-catenin is blocked by TGF-β in the presence of TCF-4 but it is resistant in the presence of LEE-1. These results suggested that enhanced, LEF-1 expression frequently observed in colon cancer might cancel TGF-β-induced repression of c-myc.Smad2D450E mutant was previously identified in colon caner. TGF-β signaling could not phosphorylate this mutant. We have shown that Smad2D450E can block phosphorylation of co-expressed wild-type Smad2 but not of Smad3, and that binding of Smad3 and Smad4 was not blocked by Smad2D450E either. However, Smad2D450E blocked the binding of Smad3 to it's target DNA and suppressed Smad3-responsive gene expression. Therefore, Smad2D450E is suggested to block Smad3 function either in the step of nuclear translocation or in the nucleus.We have examined the effects of c-Ski on the transcriptional repression of c-myc by TGF-β. c-Ski recovered transcriptional activity of c-myc suppressed by TGF-β. This function of c-Ski is not explained by known molecular function of c-Ski. We propose the novel role of c-Ski. c-Ski is suggested to compete the binding of an active Smad complex on their target DNA by extending the binding of an inactive Smad-c-Ski complex on the target DNA.

我们已经鉴定了TIE/E2 F元件，其在血清诱导的诱导和TGF-β诱导的抑制中对c-myc的转录调节至关重要。在c-myc的转录调控区也鉴定出另一个被WNT信号激活的元件TBE 3。TGF-β激活的Smad 3结合TIE/E2 F元件并使p300与E2 F-4解离。在TBE 3上，TCF-4在结合Smad 3时释放β-连环蛋白。然而，LEF-1可以同时结合β-catenin和Smad 3。因此，由β-连环蛋白激活的c-myc的转录活性在TCF-4存在下被TGF-β阻断，但在LEE-1存在下具有抗性。这些结果表明，LEF-1在结肠癌中的表达增强可能会抵消TGF-β诱导的c-myc的抑制。Smad 2D 450 E突变体先前在结肠癌中被发现。TGF-β信号不能磷酸化该突变体。我们已经表明，Smad 2D 450 E可以阻断共表达的野生型Smad 2的磷酸化，但不能阻断Smad 3的磷酸化，并且Smad 3和Smad 4的结合也不能被Smad 2D 450 E阻断。而Smad 2D 450 E阻断了Smad 3与其靶DNA的结合，抑制了Smad 3应答基因的表达。因此，Smad 2D 450 E可能在细胞核转位或细胞核内阻断Smad 3的功能。我们研究了c-Ski对TGF-β抑制c-myc转录的影响。c-Ski恢复了TGF-β抑制的c-myc转录活性。c-Ski的这种功能不能用c-Ski的已知分子功能来解释。我们提出了新的作用的c-滑雪。c-Ski被认为通过延长非活性Smad-c-Ski复合物在靶DNA上的结合来竞争活性Smad复合物在其靶DNA上的结合。