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 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.
Johnson
Nicole C
NC
University of South Florida College, Tampa 33612, USA.
Dan
Han C
HC
Cheng
Jin Q
JQ
Kruk
Patricia A
PA
D017209:Apoptosis / Q000502:physiology; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D009154:Mutation / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D019313:BRCA1 Protein; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases