The breast and ovarian cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein, which functions as a tumor suppressor gene. We present several lines of evidence for the mechanism of BRCA1 degradation through the ubiquitin-proteasome pathway by using specific inhibitors of the proteasome in human MCF-7 breast carcinoma cells. The levels of BRCA1 protein were up-regulated by proteasome inhibitors, such as MG-132 and ALLnL, suggesting rapid degradation via the ubiquitin-proteasome pathway. The enhanced loss of BRCA1 protein by taxol, okadaic acid or nocodazole treatment was prevented by the proteasome inhibitors, while inhibition of other proteases was ineffective. Accumulation and proteasomal degradation of BRCA1 protein appear to be restricted entirely to the nucleus. We also detected that high molecular weight BRCA1 protein species appeared after proteasome inhibitor treatments, which indicated that ubiquitinated species were present. Moreover the half-life of BRCA1 protein was significantly increased in response to inhibition of proteasome activity. Our present data demonstrate that BRCA1 protein may be degraded through the ubiquitin-proteasome mediated pathway.

Related Articles