The long-term objective of this proposal is to elucidate the mechanism by which BRCAI suppresses breast and ovarian cancers. Although BRCAI has been implicated in transcriptional regulation and DNA repair, its exact function in these processes remains to be understood. Even less is known concerning the tissue-specificity of BRCA 1-dependent cancer risks. Recent work in this laboratory has led to the discovery of a novel cell-type-dependent trans-activation domain in BRCA1. Furthermore, this domain specifically interacts with JunB and JunD, two AP-I proteins that are involved in negative regulation of cell proliferation. Therefore, it is hypothesized that BRCA1, by targeting specific members of the AP-1 family, modulates their functions in transcriptional regulation and cell cycle control. Disruption of the BRCA 1-Jun interaction may contribute to an elevated tissue-specific cancer risk.
The specific aims of the proposal are: 1) To determine how BRCA1 selectively binds to specific members of the AP-l family. The amino acid residues responsible for the BRCA 1-Jun interaction will be identified. The relative binding affinity of BRCAI for the different AP-1 proteins will be determined. 2) To study the functional cooperation of BRCA 1 and the Jun proteins in transcriptional regulation. Primary efforts will be focused on the role of the BRCA 1-Jun complex in the transcriptional regulation of the downstream target genes-that are involved in cell cycle control, such as cyclin Dl, p16, and p21. 3) To assess the role of the BRCAI-Jun interaction in the control of cell proliferation and stress response in breast and ovary cells. The BRCA 1-Jun complex formation during the normal cell cycle and stress response will be investigated. Various cell biological assays will be utilized to determine the cooperation between BRCAI and the Jun proteins in cell cycle control and anti-oncogenesis. The proposed study promises to shed new insights into the functional connection between BRCAI and the Jun proteins. It will also provide potential therapeutic targets for correcting the defects caused by BRCAI mutations.
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