title: The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release.
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.
authors: 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.
authors: Serena C
authors: SC
authors: Hedgepeth
authors: 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.
authors: M Iveth
authors: MI
authors: Garcia
authors: the Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642.
authors: Larry E
authors: LE
authors: Wagner
authors: the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Ana M
authors: AM
authors: Rodriguez
authors: the Department of Biology, Penn State University, University Park, Pennsylvania, 16802, and.
authors: Sree V
authors: SV
authors: Chintapalli
authors: the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Russell R
authors: RR
authors: Snyder
authors: the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Gary D V
authors: GD
authors: Hankins
authors: the Centre for Cancer Research, Westmead Millennium Institute at Westmead Hospital, The University of Sydney, Westmead, New South Wales 2145, Australia.
authors: Beric R
authors: BR
authors: Henderson
authors: the Centre for Cancer Research, Westmead Millennium Institute at Westmead Hospital, The University of Sydney, Westmead, New South Wales 2145, Australia.
authors: Kirsty M
authors: KM
authors: Brodie
authors: the Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642.
authors: David I
authors: DI
authors: Yule
authors: the Department of Biology, Penn State University, University Park, Pennsylvania, 16802, and.
authors: Damian B
authors: DB
authors: van Rossum
authors: From the Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, Texas 77030, Darren.F.Boehning@uth.tmc.edu.
authors: Darren
authors: D
authors: Boehning
mesh_terms: D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002118:Calcium
keywords: Apoptosis; BRCA1; Calcium; Cancer; Inositol 1,4,5-Trisphosphate Receptor (IP3R); Lipid; Lipid Binding
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