Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes

Most of the activities of IFN-gamma are the result of STAT1-mediated transc riptional responses. In this study, we show that the BRCA1 tumor suppressor acts in concert with STAT1 to differentially activate transcription of a s ubset of IFN-gamma target genes and mediates growth inhibition by this cyto kine. After IFN-gamma treatment, induction of the cyclin-dependent kinase i nhibitor, p21WAF1, was synergistically activated by BRCA1. whereas the IRF- 1 gene was unaffected. Importantly, the differential induction of p21WAF1 w as impaired in breast cancer cells homozygous for the mutant BRCA1 5382C al lele. Biochemical analysis illustrated that the mechanism of this transcrip tional synergy involves interaction between BRCA1 aa 502-802 and the C-term inal transcriptional activation domain of STAT1: including Ser-727 whose ph osphorylation is crucial for transcriptional activation. Significantly, STA T1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the import ance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins. These findings reveal a novel mechanism for BRCA1 function in the IFN-gamma-dependent tumor surveillance system.