The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release

Serena C. Hedgepeth, M. Iveth Garcia, Larry E. Wagner, Ana M. Rodriguez, Sree V. Chintapalli, Russell R. Snyder, Gary D.V. Hankins, Beric R. Henderson, Kirsty M. Brodie, David I. Yule, Damian B. Van Rossum, Darren Boehning

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34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7304-7313
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number11
DOIs
StatePublished - Mar 13 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hedgepeth, S. C., Garcia, M. I., Wagner, L. E., Rodriguez, A. M., Chintapalli, S. V., Snyder, R. R., Hankins, G. D. V., Henderson, B. R., Brodie, K. M., Yule, D. I., Van Rossum, D. B., & Boehning, D. (2015). The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release. Journal of Biological Chemistry, 290(11), 7304-7313. https://doi.org/10.1074/jbc.M114.611186