The steroid receptor co-activator-1 (SRC-1) potentiates TGF-beta/Smad signaling: role of p300/CBP.
The three related 160-kDa proteins, SRC-1, TIF-2 and RAC-3, were initially identified as factors interacting with nuclear receptors. They have also been reported to potentiate the activity of other transcription factors such as AP-1 or NF-kappaB. The aim of this work was to identify whether SRC-1 interferes with the TGF-beta/Smad ... signaling pathway, and if so, to identify its underlying mechanisms of action. Using transient cell transfection experiments performed in human dermal fibroblasts with the Smad3/4-specific (SBE)4-lux reporter construct, as well as the human PAI-1 promoter, we determined that SRC-1 enhances TGF-beta-induced, Smad-mediated, transcription. Likewise, SRC-1 overexpression potentiated TGF-beta-induced upregulation of PAI-1 steady-state mRNA levels. Using a mammalian two-hybrid system, we demonstrated that SRC-1 interacts with the transcriptional co-activators p300/CBP, but not with Smad3. Overexpression of the adenovirus E1A oncoprotein, an inhibitor of CBP/p300 activity, prevented the enhancing effect of SRC-1 on Smad3/4-mediated transcription, indicating that p300/CBP may be required for SRC-1 effect. Such hypothesis was validated, as expression of a mutant form of SRC-1 lacking the CBP/p300-binding site failed to upregulate Smad3/4-dependent transcription, while full-length SRC-1 potentiated p300.Smad3 interactions. These results identify SRC-1 as a novel Smad3/4 transcriptional partner, facilitating the functional link between Smad3 and p300/CBP.
Mesh Terms:
Cell Line, DNA-Binding Proteins, Fibroblasts, Genes, Reporter, Histone Acetyltransferases, Humans, Infant, Newborn, Male, Nuclear Proteins, Nuclear Receptor Coactivator 1, Plasmids, Signal Transduction, Skin, Smad Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Transforming Growth Factor beta
Cell Line, DNA-Binding Proteins, Fibroblasts, Genes, Reporter, Histone Acetyltransferases, Humans, Infant, Newborn, Male, Nuclear Proteins, Nuclear Receptor Coactivator 1, Plasmids, Signal Transduction, Skin, Smad Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Transforming Growth Factor beta
Oncogene
Date: Mar. 10, 2005
PubMed ID: 15688032
View in: Pubmed Google Scholar
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