BRCA1: RB Interaction in Breast Cancer Suppression
Abstract
Germilne mutations of BRCAl confer an increased risk for breast and ovarian cancer in women and prostate cancer in men. Recent studies suggest that the tumor suppressor activity of BRCAl is due, in part, to physical/functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein. Two RB binding sites on BRCAl were identified, one in the C-terminal BRCT domain and one in the N-terminus, between aa 304 and 394 (Yarden and Brody, PNAS USA 96: 4983-4988, 1999; Aprelikova et al. PNAS USA 96: 11866-11871, 1999). The N-terminal region of BRCAl contains a consensus RB binding motif (sup35 8 LXCXE), but the role of this site in mediating RB binding and BRCAl/RB functional activity is unknown. Our studies indicate that the BRCAl interacts with RB, through a binding site between aa 302 and 440, but the binding is not dependent on the LXCXE motif. Nor does the interaction require an intact A/B binding pocket of RB. Transient or stable expression of a wild-type BRCAl gene (wtBRCAl) ,,caused down-regulation of expression of RB, p107 and pl3O, associated with a chemosensitivity to DNA-damaging agents. In contrast, expression of an LXCXE-defective BRCAl mutant (LXCXE -> RXRXH) did not cause down-regulation of the RB proteins and the induction of chemoresistance. Our findings suggest that some biologic functions of BRCAl (eg., chemosensitization) are due, in part, to down-regulation of RB family proteins mediated by an LXCXE site embedded within the N-terminal RB binding site.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA405258
Entities
People
- Saijun Fan