| Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-beta involves functional cooperation with p300/CBP transcriptional coactivators. | |
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MedLine Citation:
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PMID: 10918613 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Transforming growth factor-beta (TGF-beta) stimulation of Type I collagen gene (COL1A2) transcription involves the Smad signal transduction pathway, but the mechanisms of Smad-mediated transcriptional activation are not fully understood. We now demonstrate that the ubiquitous transcriptional coactivators p300 and CREB-binding protein (CBP) enhanced basal as well as TGF-beta- or Smad3-induced COL1A2 promoter activity, and stimulated the expression of endogenous Type I collagen. The adenoviral E1A oncoprotein abrogated stimulation of COL1A2 activity in transfected fibroblasts, and reduced the basal level of collagen gene expression. This effect was due to specific interaction of E1A with cellular p300/CBP because (a) a mutant form of E1A defective in p300 binding failed to abrogate stimulation, and (b) forced expression of p300/CBP restored the ability of TGF-beta to stimulate COL1A2 promoter activity in the presence of E1A. The effect of p300 on COL1A2 transcription appeared to be due, in part, to its intrinsic acetyltransferase activity, as stimulation induced by a histone acetyltransferase-deficient mutant p300 was substantially reduced. Transactivation of COL1A2 by p300 involved the Smad signaling pathway, as Smad4-deficient cells failed to respond to p300, and stimulation was rescued by overexpression of Smad4. Furthermore, minimal constructs containing only the Smad-binding CAGACA element of COL1A2 were transactivated by p300 in the presence of TGF-beta. These results indicate, for the first time, that the multifunctional p300/CBP coactivators play a major role in Smad-dependent TGF-beta stimulation of collagen gene expression in fibroblasts. Oncogene (2000) 19, 3546 - 3555 |
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Authors:
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A K Ghosh; W Yuan; Y Mori; J Varga |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Oncogene Volume: 19 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2000 Jul |
Date Detail:
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Created Date: 2000-08-24 Completed Date: 2000-08-24 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 3546-55 Citation Subset: IM |
Affiliation:
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Section of Rheumatology, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenovirus E1A Proteins
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physiology* Binding Sites Cells, Cultured Collagen / biosynthesis, genetics* DNA-Binding Proteins / deficiency, genetics, physiology* Fibroblasts / drug effects, metabolism* Gene Expression Regulation / drug effects* Humans Nuclear Proteins / chemistry, deficiency, genetics, physiology* Promoter Regions, Genetic Protein Binding Recombinant Fusion Proteins / physiology Signal Transduction / drug effects Skin / cytology Smad3 Protein Smad4 Protein Trans-Activators / chemistry, deficiency, genetics, physiology* Transcriptional Activation* Transfection Transforming Growth Factor beta / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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AR-42309/AR/NIAMS NIH HHS; AR-46390/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adenovirus E1A Proteins; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Recombinant Fusion Proteins; 0/SMAD3 protein, human; 0/SMAD4 protein, human; 0/Smad3 Protein; 0/Smad4 Protein; 0/Trans-Activators; 0/Transforming Growth Factor beta; 9007-34-5/Collagen |
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