TY - JOUR
T1 - The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release
AU - Hedgepeth, Serena C.
AU - Garcia, M. Iveth
AU - Wagner, Larry E.
AU - Rodriguez, Ana M.
AU - Chintapalli, Sree V.
AU - Snyder, Russell R.
AU - Hankins, Gary D.V.
AU - Henderson, Beric R.
AU - Brodie, Kirsty M.
AU - Yule, David I.
AU - Van Rossum, Damian B.
AU - Boehning, Darren
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/3/13
Y1 - 2015/3/13
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M114.611186
DO - 10.1074/jbc.M114.611186
M3 - Article
C2 - 25645916
AN - SCOPUS:84924897990
SN - 0021-9258
VL - 290
SP - 7304
EP - 7313
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -