BRCA1-induced Apoptosis Involves Inactivation of ERK1/2 Activities

• Published in: The Journal of biological chemistry 2002-09, Vol.277 (36), p.33422-33430
• Main Authors: Yan, Ying, Haas, John P., Kim, Min, Sgagias, Magdalene K., Cowan, Kenneth H.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Apoptosis; BRCA1 Protein - metabolism; Caspase 8; Caspase 9; Caspases - metabolism; Cell Division; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fas Ligand Protein; fas Receptor - metabolism; G2 Phase; Genes, BRCA1; Genes, Dominant; Humans; Immunoblotting; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Membrane Glycoproteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Mitosis; Phosphorylation; Signal Transduction; Time Factors; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M201147200

Mutation in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer. Recent studies have shown that the BRCA1 gene product may be important in mediating responses to DNA damage and genomic instability. Previous studies have indicated that overexpression of BRCA1 can induce apoptosis or cell cycle arrest at the G2/M border in various cell types. Although the activation of JNK kinase has been implicated in BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase family in mediating the cellular response to BRCA1 has not yet been examined. In this study, we monitored the activities of three members of the MAPK family (ERK1/2, JNK, p38) in MCF-7 breast cancer cells and U2OS osteosarcoma cells after their exposure to a recombinant adenovirus expressing wild type BRCA1 (Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at the G2/M border; however, BRCA1 expression in U2OS cells induced apoptosis. Although BRCA1 induced JNK activation in both cell lines, there were marked differences in ERK1/2 activation in response to BRCA1 expression in these two cell lines. BRCA1-induced apoptosis in U2OS cells was associated with no activation of ERK1/2. In contrast, BRCA1 expression in MCF-7 cells resulted in the activation of both ERK1/2 and JNK. To directly assess the role of ERK1/2 in determining the cellular response to BRCA1, we used dominant negative mutants of MEK1 as well as MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2 activation resulted in increased apoptosis after BRCA1 expression in MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of JNK, induction of Fas-L/Fas interaction, and activation of caspases 8 and 9. The studies presented in this report indicate that the response to BRCA1 expression is determined by the regulation of both the JNK and ERK1/2 signaling pathways in cells.