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The BRCA1 Tumor Suppressor Binds to Inositol 1,4,5-Trisphosphate Receptors to Stimulate Apoptotic Calcium Release*

Serena C. Hedgepeth,Serena C. Hedgepeth,M. I. Garcia,M. I. Garcia,Larry E. Wagner,Ana M. Rodriguez,S. Chintapalli,R. Snyder,G. Hankins,B. Henderson,Kirsty M Brodie,D. Yule,D. B. Rossum,D. Boehning

Published 2015 in Journal of Biological Chemistry

ABSTRACT

Background: The non-nuclear BRCA1 tumor suppressor can stimulate cell death, but the mechanisms are unknown. Results: BRCA1 binds to the inositol 1,4,5-trisphophate receptor (IP3R) calcium channel at the endoplasmic reticulum to stimulate apoptotic calcium release. Conclusion: BRCA1 tumor suppressor activity includes direct stimulation of apoptotic cell death via increased IP3R activity. Significance: We identify a novel role for the tumor suppressor BRCA1. The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein.

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