The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: Role of p300/CBP

• Autores: Dennler, S.; Pendaries, V.; Tacheau, C.; Costas, M.A.; Mauviel, A.; Verrecchia, F.
• Año de publicación: 2005
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Oncogene 2005;24(11):1936-1945
• Materia: p300; Smad; SRC-1 TGF-β; E1A protein; messenger RNA; oncoprotein; protein p300; recombinant transforming growth factor beta1; Smad protein; Smad3 protein; Smad4 protein; steroid receptor coactivator 1; virus protein; DNA binding protein; histone acetyltransferase; nuclear protein; Smad protein; steroid receptor coactivator 1; transactivator protein; transcription factor; transforming growth factor beta; Adenovirus; apoptosis; article; dermis; DNA binding; gel mobility shift assay; gene overexpression; genetic transcription; genetic transfection; human; human cell; nonhuman; Northern blotting; plasmid; priority journal; protein protein interaction; reporter gene; signal transduction; skin fibroblast; cell line; fibroblast; male; metabolism; newborn; physiology; skin; Adenoviridae; Mammalia; Cell Line; DNA-Binding Proteins; Fibroblasts; Genes, Reporter; Histone Acetyltransferases; Humans; Infant, Newborn; Male; Nuclear Proteins; Plasmids; Signal Transduction; Skin; Smad Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic; Transfection; Transforming Growth Factor beta
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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-κB. The aim of this work was to identify whether SRC-1 interferes with the TGF-β/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-β-induced, Smad-mediated, transcription. Likewise, SRC-1 overexpression potentiated TGF-β-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. © 2005 Nature Publishing Group All rights reserved.
Fil:Costas, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.