1998 Fiscal Year Final Research Report Summary
Autocrine growth inhibitors of keratinocytes and their significance in carcinogenesis
| Project/Area Number |
09670243
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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 |
Experimental pathology
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
KATO Mitsuyasu Japanese Foundation for Cancer Research, The Cancer Institute, Department of Biochemistry Fellow, 癌研究所・生化学部, 研究員 (20194855)
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| Project Period (FY) |
1997 – 1998
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| Keywords | keratinocyte / cancer / transforming growth factor-beta / SMAD / growth inhibition / autocrine / invasive growth |
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| Research Abstract |
(1) Functions of TGF-beta pathway-restricted SMADs : We identified a splice variant of Smad2 which omitted exon 3.Smad2DELTAexon3 had a transcriptional activity more potent than wild-type Smad2 and similar to Smad3, when p3TP-lux was used as a reporter.Smad2DELTAexon3 had an activity to bind to a Smad binding element in the p3TP promoter, which Smad3 can bind to but Smad2 can not.These results suggested that the peptide coded by exon 3 of Smad2 interfered with the direct DNA binding of Smad2.We also found that TGF-beta activated both Smad2 and Smad3 in HaCaT cells, and activin activated Smad3 as potent as TGF-beta did, but the activation of Smad2 by activin was less potent than that by TGF-beta.
(2) Inhibition of TGF-beta signals by a mutant Smad3 : A mutation of Smad2 identified in a case of colon cancer was reconstructed on the corresponding residue of Smad3.This mutant Smad3D407E had a dominant negative effect on TGF-beta signals.Expression of Smad3D407E conferred invasive growth potential on HaCaT cells as well as resistance to the growth inhibitory effects of TGF-beta.
(3) Disruption of TGF-beta signals in cancer cells : Patients of papillary thyroid microadenocarcinoma with a positive staining for TGF-beta in the primary lesions had higher incidence of distant metastasis than negative cases.
(4) Target genes of TGF-beta signals : c-Myc was identified to be an essential target of SMADs in growth inhibitory signals of TGF-beta in keratinocytes.We also identified a new early responsive gene to TGF-beta.This gene coded a nuclear protein of 19 kDa with an isoelectric point of 10.9.
(5) Physiological function of TGF-beta signals : TGF-beta was suggested to be involved in epithelial cell migration during the corneal wound healing process.
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