BRCA2 and Smad3 synergize in regulation of gene transcription

• Published in: Oncogene Vol. 21; no. 36; pp. 5660 - 5664
• Main Authors: PREOBRAZHENSKA, Olena, YAKYMOVYCH, Mariya, KANAMOTO, Takashi, YAKYMOVYCH, Ihor, STOIKA, Rostyslav, HELDIN, Carl-Henrik, SOUCHELNYTSKYI, Serhiy
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 15.08.2002; Nature Publishing Group
• Subjects: Binding Sites; Biological and medical sciences; Blotting, Western; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms/genetics/metabolism; Cell cycle; Cell growth; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins/genetics/metabolism; Drug Synergism; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genes, Reporter - genetics; Glutathione Transferase - metabolism; Growth factors; Humans; Intracellular signalling; Localization; Medicin och hälsovetenskap; Molecular and cellular biology; Molecular genetics; Mutation; Ovarian cancer; Ovaries; Plasmids; Plasminogen activator inhibitors; Prostate cancer; Protein Binding; Signal Transduction; Smad3 Protein; Synergism; Trans-Activation (Genetics); Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators/genetics/metabolism; Transcription activation; Transcription factors; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Transcriptional Activation; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta/metabolism/pharmacology; Transforming growth factor-b; Transforming growth factor-b1; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; Ukraine; Regulation(control); Smad protein; Smad3; Transcription; BRCA2; Carcinogenesis; Tumor suppressor gene; Western; Tumor Cells; Genes; Reporter/genetics; Gene Expression Regulation; Genetic; Cultured; Blotting; Neoplastic
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/sj.onc.1205732

Smad3 is an essential component in the intracellular signaling of transforming growth factor-beta (TGFbeta), which is a potent inhibitor of tumor cell proliferation. BRCA2 is a tumor suppressor involved in early onset of breast, ovarian and prostate cancer. Both Smad3 and BRCA2 possess transcription activation domains. Here, we show that Smad3 and BRCA2 interact functionally and physically. We found that BRCA2 forms a complex with Smad3 in vitro and in vivo, and that both MH1 and MH2 domains of Smad3 contribute to the interaction. TGFbeta1 stimulates interaction of endogenous Smad3 and BRCA2 in non-transfected cells. BRCA2 co-activates Smad3-dependent transcriptional activation of luciferase reporter and expression of plasminogen activator inhibitor-1 (PAI-1). Smad3 increases the transcriptional activity of BRCA2 fused to the DNA-binding domain (DBD) of Gal4, and reciprocally, BRCA2 co-activates DBD-Gal4-Smad3. Thus, our results show that BRCA2 and Smad3 form a complex and synergize in regulation of transcription.