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 II¶,
- 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** and
- Darren Boehning‡1
- From the ‡Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, Texas 77030,
- the §Cell Biology Graduate Program and
- the ‖Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555,
- the ¶Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642,
- the **Department of Biology, Penn State University, University Park, Pennsylvania, 16802, and
- the ‡‡Centre for Cancer Research, Westmead Millennium Institute at Westmead Hospital, The University of Sydney, Westmead, New South Wales 2145, Australia
- ↵1 To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, 6431 Fannin St., MSB Suite 6.161, Houston TX 77030. Tel.: 281-500-6167; Fax: 713-500-0652; E-mail: Darren.F.Boehning{at}uth.tmc.edu.
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.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant GM081685 (to D. B.) and by National Institutes of Health Grant DE014756 (to D. I. Y.). This work was also supported by seed funds provided by the Department of Obstetrics and Gynecology, University of Texas Medical Branch (Galveston, TX) and startup funds provided by the Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston (Houston, TX) (to D. B.); by Cancer Institute of New South Wales, Australia Grant 12/CDF/2-12 (to B. R. H.); and by a grant from the Pennsylvania Department of Health using tobacco settlement funds (to D. V. R.).
- Received September 11, 2014.
- Revision received January 29, 2015.
- © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
