The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/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-κB. The aim of this work was to identify whether SRC-1 interf...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2005 |
| País: | Argentina |
| Institución: | Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales |
| Repositorio: | Biblioteca Digital (UBA-FCEN) |
| Idioma: | inglés |
| OAI Identifier: | paperaa:paper_09509232_v24_n11_p1936_Dennler |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_09509232_v24_n11_p1936_Dennler |
| Access Level: | acceso abierto |
| Palabra clave: | 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 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 |
| Sumario: | 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. |
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