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

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 ce...

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Bibliographic Details
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
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Summary: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.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2004.04.003