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

Exp Cell Res. 2004 Aug 1;298(1):9-16. doi: 10.1016/j.yexcr.2004.04.003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • 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
  • 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

Substances

  • BRCA1 Protein
  • Inhibitor of Apoptosis Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Ubiquitin
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • Caspase 3
  • Caspases