DIFFERENTIAL TRANSCRIPTIONAL ACTIVATION BY THE N-TERMINAL REGION OF BRCA1 SPLICE VARIANTS BRCA1A AND BRCA1B

The breast and ovarian cancer susceptibility gene BRCA1, is a nuclear phosphoprotein which functions as a tumor suppressor in human breast c ancer cells. BRCA1 protein contains an amino-terminal zinc finger moti f and a carboxy-terminal acidic region. Recently, the carboxyterminal region of BRCA1 and the amino-terminal region of BRCA2 proteins were s hown to function as transactivation domains when fused to GAL4 DNA bin ding domain. We have recently isolated and characterized two new natur ally occurring variants of BRCA1 (BRCA1a/p110 and BRCA1b/p100) which a re phosphoproteins containing phosphotyrosine that associate with E2F transcriptional factors, cyclins and cyclin dependent kinases indicati ng a role for BRCA1 proteins in cell-cycle regulation. Here we show fo r the first time that the aminoterminal region of BRCA1a (BNT) but not BRCA1b can also function as a transcriptional activator when fused to GAL4 DNA binding domain. Thus, BRCA1/1a proteins contain two autonomo us transcriptional activation domains, one at the amino-terminal regio n (BNT) and the other at the carboxyterminal region (BCT). BRCA1b reta ins only the BCT domain since it has lost part of the potential BNT do main as a result of alternative splicing. Our results also suggest the presence of an inhibitory domain at the carboxy terminal region of BR CA1 and BRCA1a proteins (BID). Thus, BRCA1b protein may function as a dominant negative variant that could regulate the transcriptional acti vity of BRCA1/BRCA1a proteins and hence may serve as a marker for iden tifying individuals with greater potential for developing breast cance r. It may be possible that loss of transcriptional activation or prote in-protein interactions in patients with mutations in the amino termin al zinc finger domain could deprive the cell of an important mechanism for regulating cell proliferation leading to the development of breas t cancer.