BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene.
The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in breast tumorigenesis and is overexpressed in most primary tumors. BRCA1 is a transcription factor involved in numerous cellular processes, including DNA damage repair, cell growth, and apoptosis. Consistent with its tumor suppressor role, we demonstrated that BRCA1 repressed the activity of co-transfected IGF-IR promoter reporter constructs in a number of breast cancer-derived cell lines. Results of electrophoretic mobility shift assay showed that BRCA1 did not exhibit any specific binding to the IGF-IR promoter, although it prevented binding of Sp1. Co-immunoprecipitation experiments demonstrated that BRCA1 action was associated with specific interaction with Sp1 protein. Furthermore, using a series of glutathione S-transferase-tagged BRCA1 fragments, we mapped the Sp1-binding domain to a segment located between aa 260 and 802. In summary, our data suggest that the IGF-IR gene is a novel downstream target for BRCA1 action.
Abramovitch
Shirley
S
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
Glaser
Tova
T
Ouchi
Toru
T
Werner
Haim
H
D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D016329:Sp1 Transcription Factor; D017526:Receptor, IGF Type 1