BRCA1 185delAG mutation inhibits Akt-dependent, IAP-mediated caspase 3 inactivation in human ovarian surface epithelial cells

• Published in: Experimental cell research 2004-08, Vol.298 (1), p.9-16
• Main Authors: Johnson, Nicole C, Dan, Han C, Cheng, Jin Q, Kruk, Patricia A
• Format: Article
• Language: English
• Subjects: Akt; Apoptosis; Apoptosis - physiology; BRCA1; BRCA1 Protein - biosynthesis; BRCA1 Protein - genetics; Carcinoma - enzymology; Carcinoma - genetics; Caspase 3; Caspases - metabolism; Down-Regulation - genetics; Epithelial Cells - cytology; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Female; Gene Expression Regulation, Enzymologic - genetics; Hereditary ovarian cancer; Humans; Inhibitor of Apoptosis Proteins; Mutation - genetics; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovary - cytology; Ovary - enzymology; Ovary - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction - genetics; Ubiquitin - metabolism; X-Linked Inhibitor of Apoptosis Protein; XIAP
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2004.04.003

BRCA1 mutations have long been associated with altered apoptosis. We have recently reported that caspase 3 activation is increased in human ovarian surface epithelial (OSE) cells expressing a germline N-terminal BRCA1 185delAG mutation. Here, we report increased caspase 3 activity in 185delAG OSE cells associated with decreased expression of cIAP-1 and X-linked inhibitor of apoptosis (XIAP), and decreased ubiquitination of caspase 3. Overexpression of XIAP restored active caspase 3 ubiquitination and lowered levels of caspase 3 activity. Further, the BRCA1 185delAG mutation was associated with reduced levels of phosphorylated Akt1. Transfection with activated Akt1 led to increased cIAP-1 and XIAP levels similar to that seen in BRCA1 185delAG cell lines. Taken together, these data suggest a direct link between the BRCA1 185delAG mutation and alterations in the caspase-mediated apoptotic pathway.