BRCA1 activation of the GADD45 promoter

Breast cancer susceptibility gene BRCA1 has been implicated in the control of gene regulation and such regulated genes are thought to mediate the biol ogical role of BRCA1. Overexpression of BRCA1 induces GADD45, a p53-regulat ed and stress-inducible gene. However, the molecular mechanism by which BRC A1 induces the expression GADD45 remains unclear. In this report, we have s hown that the GADD45 promoter is strongly activated following expression of wild-type BRCA1, In contrast, both the tumor-derived BRCA1 mutants (p1749R and Y1853insA) and truncated BRCA1 mutant protein (Delta 500-1863 BRCA1), which lack transactivation activity, were unable to activate the GADD45 pro moter, indicating that the BRCA1-mediated activation of the GADD45 promoter requires normal transcriptional properties of BRCA1. BRCA1 did not induce the c-Jun and c-fos promoters, which rules out a general effect of BRCA1 on other immediate-responsive genes. Expression of the human papillomavirus E 6 and the dominant-negative mutant p53 proteins had no effect on the induct ion of the GADD45 promoter by BRCA1, suggesting that activation of the GADD 45 promoter by BRCA1 is independent of cellular p53 function. With the 5'-d eletion analysis, the BRCA1-responsive element of the GADD45 promoter was m apped at the region from -121 to -75. Disruption of this region resulted in the abrogation of BRCA1 activation of the GADD45 promoter. Taken together, these results demonstrate that the mechanism by which BRCA1 induces GADD45 is mainly through the transactivation of the GADD45 promoter, further demo nstrating the evidence that GADD45 acts as one of the BRCA1-regulated genes .