2000 Fiscal Year Final Research Report Summary
Signal transduction of the TGF-βsuperfamily and its disturbances.
| Project/Area Number |
11670136
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
MASAHIRO Kawabata The Cancer Institute, Biochemistry, Japanese Foundation for Cancer Research Associate Member, 癌研究所・生化学部, 主任研究員 (60224838)
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| Co-Investigator(Kenkyū-buntansha) |
KEN Yagi The Cancer Institute, Biochemistry, Japanese Foundation for Cancer Research Associate, 癌研究所・生化学部, 研究員 (10322637)
HIROFUMI Inoue The Cancer Institute, Biochemistry, Japanese Foundation for Cancer Research Associate, 癌研究所・生化学部, 研究員 (70321635)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Smad / TGF-β / BMP / LIF / p300 / c-Ski / E1A |
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| Research Abstract |
(1) We identified a novel Drosophila Smad, dSmad2, proving that invertebrates have the TGF-β/activin signal transduction pathway. We also showed that Shn and Mad, both of which are downstream of a member of the TGF-β superfamily in Drosophila, interact with each other upon receptor stimulation.
(2) We showed that Smad1, which is downstream of BMP, forms a complex with STAT3, which is downstream of LIE, via p300, and that they synergistically induce the expression of their target gene.
(3) Smad3 interacts with PEBP2a. The synergism of both factors is essential to the transactivation of the immunogloblin Ca promoter.
(4) We studied the interactiono of Smad with p300, a transcriptional coactivator, and identified the Smad binding domain in p300. We found that E1A binds to Smad, thereby inhibiting TGF-β signaling.
(5) We isolated c-Ski as a Smad2 binding protein through a two-hybrid screening. Smad recruits HDAC, a histone deacetylase, via c-Ski, which represses TGF-β-dependent transcription. Thus it was revealed that Smad can both activate and repress transcription depending upon its interacting proteins.
(6) We made gene knock-out mice of the BMP type II receptor. The result showed that the receptor plays a crucial role in early development.
(7) We made a reporter containing multiple repeats of GCCGnCGC (GCCG box), which responded to BMP and the transactivation did not depend upon cell types. Thus the reporter is a useful system to detect BMP signals.
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