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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
50
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pubmed:dateCreated |
2001-1-8
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pubmed:abstractText |
Transforming growth factor-beta1 (TGFbeta) is a strong activator of extracellular matrix accumulation. TGFbeta stimulates the gene coding for human alpha2(I)-collagen (COL1A2) by inducing binding of an Sp1-containing complex to an upstream promoter element (TGFbeta responsive element or TbRE) that contains a CAGA box. Here we report that the CAGA box of the TbRE is the binding site of the Smad3/Smad4 complex, and that the binding of the complex is required for TGFbeta-induced COL1A2 up-regulation. Recombinant Smad3 and Smad4 bind in vitro to the CAGA box of COL1A2; TGFbeta treatment of cultured fibroblasts induces Smad3/Smad4 binding to the TbRE; transient overexpression of Smad3 and Smad4 in fibroblasts transactivates TbRE-driven transcription; and COL1A2 gene up-regulation by TGFbeta is abolished in cells stably transfected with plasmids that express dominant negative forms of Smad3 or Smad4. In Sp1-deficient Drosophila Schneider cells, there was cooperative synergy between Smad3/Smad4 and Sp1 at the TbRE site. The analysis also emphasized the requirement of both Sp1- and Smad-binding sites for optimal promoter transactivation. In cells stably transfected with a plasmid expressing a dominant negative form of Sp1, the synergy was shown to be promoter-specific and dependent on the binding of Sp1 to the TbRE. Interestingly, overexpression of dominant negative Sp1 was found to block the antagonistic signal of tumor necrosis factor-alpha on COL1A2 transcription, as well. These results provide the first linkage between the Smad3 and Smad4 proteins and TGFbeta stimulation of type I collagen biosynthesis.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Collagen,
http://linkedlifedata.com/resource/pubmed/chemical/Collagen Type I,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Sp1 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/TGFB1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tgfb1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta1,
http://linkedlifedata.com/resource/pubmed/chemical/alpha 2(I) collagen
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
275
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
39237-45
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:11007770-3T3 Cells,
pubmed-meshheading:11007770-Animals,
pubmed-meshheading:11007770-Base Sequence,
pubmed-meshheading:11007770-Binding Sites,
pubmed-meshheading:11007770-Blotting, Northern,
pubmed-meshheading:11007770-Blotting, Western,
pubmed-meshheading:11007770-Collagen,
pubmed-meshheading:11007770-Collagen Type I,
pubmed-meshheading:11007770-DNA-Binding Proteins,
pubmed-meshheading:11007770-Genes, Dominant,
pubmed-meshheading:11007770-Humans,
pubmed-meshheading:11007770-Mice,
pubmed-meshheading:11007770-Models, Genetic,
pubmed-meshheading:11007770-Molecular Sequence Data,
pubmed-meshheading:11007770-Promoter Regions, Genetic,
pubmed-meshheading:11007770-Protein Binding,
pubmed-meshheading:11007770-Recombinant Proteins,
pubmed-meshheading:11007770-Response Elements,
pubmed-meshheading:11007770-Signal Transduction,
pubmed-meshheading:11007770-Smad3 Protein,
pubmed-meshheading:11007770-Smad4 Protein,
pubmed-meshheading:11007770-Sp1 Transcription Factor,
pubmed-meshheading:11007770-Trans-Activators,
pubmed-meshheading:11007770-Transcription, Genetic,
pubmed-meshheading:11007770-Transcriptional Activation,
pubmed-meshheading:11007770-Transfection,
pubmed-meshheading:11007770-Transforming Growth Factor beta,
pubmed-meshheading:11007770-Transforming Growth Factor beta1,
pubmed-meshheading:11007770-Up-Regulation
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pubmed:year |
2000
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pubmed:articleTitle |
Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I)-collagen (COL1A2) transcription.
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pubmed:affiliation |
Brookdale Center, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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