2003 Fiscal Year Final Research Report Summary
Transcriptional regulation of the target genes of transforming growth factor-β and it's abnormalities in disease.
| Project/Area Number |
14570208
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | University of Tsukuba |
|---|
Principal Investigator |
KATO Mitsuyasu University of Tsukuba, INSTITUTE OF BASIC MEDICAL SCIENCES, PROFESSOR, 基礎医学系, 教授 (20194855)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | TGF-β / Smad / transcription / c-myc / WNT / TCF-4 / LEF-1 / c-Ski |
|---|
| Research Abstract |
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.
|
Research Products
(10 results)
