Proteasome-mediated degradation of BRCA1 protein in MCF-7 human breast cancer cells

The breast and ovarian cancer susceptibility gene BRCA1 encodes a nuclear p hosphoprotein, which functions as a tumor suppressor gene. We present sever al lines of evidence for the mechanism of BRCA1 degradation through the ubi quitin-proteasome pathway by using specific inhibitors of the proteasome in human MCF-7 breast carcinoma cells. The levels of BRCA1 protein were upreg ulated by proteasome inhibitors, such as MG-132 and ALLnL, suggesting rapid degradation via the ubiquitinproteasome pathway. The enhanced loss of BRCA 1 protein by taxol, okadaic acid or nocodazole treatment was prevented by t he proteasome inhibitors, while inhibition of other proteases was ineffecti ve. Accumulation and proteasomal degradation of BRCA1 protein appear to be restricted entirely to the nucleus. We also detected that high molecular we ight 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 ma y be degraded through the ubiquitin-proteasome mediated pathway.