The goal of the research described in this proposal is to contribute to our understanding of breast cancer by characterizing the basic functional mechanism of the BRCA2 breast cancer susceptibility gene. The BRCA2 breast cancer susceptibility gene is thought to function as a transcription factor and may also play a role in DNA repair, as suggested by the interaction between BRCA2 and Rad51. The applicant proposes to characterize the interaction between the BRCA2, p21 and p53 tumor suppressors. The p21 cell cycle inhibitor and p53 have been implicated in many of the growth regulatory pathways of the cell, including cell cycle control and DNA repair. His hypothesis is that BRCA is also intimately involved in these cellular pathways as a G1/S checkpoint control molecule through its ability to induce p21 expression in a p53 dependent and independent manner. BRCA2 induction of p21 may (i) inhibit the cell cycle and slow cell growth, and (ii) pause the cell cycle and DNA replication in response to DNA damage to allow DNA repair to take place. The domains of BRCA2 and p53 required to induce p21 will be mapped, as will the BRCA2 response element of the p21 promoter. The interaction will then be studied by reconstitution experiments to define its role in cell growth regulation, cell cycle control, and response to DNA damage. Little is known about control of the cell cycle and DNA repair in mammalian systems, and it is possible that BRCA2 is the key to characterization of these systems. If we can clearly define even one of the mechanisms of action of BRCA2, in this case the BRCA2/p21/p53 interaction, then this understanding should translate into the development of genetic and pharmacological intervention for breast and other cancers.
| Thangaraju, M; Kaufmann, S H; Couch, F J (2000) BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. J Biol Chem 275:33487-96 |
