Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1

The breast cancer susceptibility gene BRCA1 encodes a protein implicated in the cellular response to DNA damage, with postulated roles in homologous r ecombination as well as transcriptional regulation. To identify downstream target genes, we established cell lines with tightly regulated inducible ex pression of BRCA1. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A maj or BRCA1 target is the DNA damage-responsive gene GADD45. Induction of BRCA 1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-a ctivated protein kinase (JNK/SAPK), a signaling pathway potentially linked to GADD45 gene family members. The p53-independent induction of GADD45 by B RCA1 and its activation of JNK/SAPK suggest a pathway for BRCA1-induced apo ptosis.