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 Rodriguez, Sree V. Chintapalli, Russell Snyder, Gary Hankins, Beric R. Henderson, Kirsty M. Brodie, David I. Yule, Damian B. Van Rossum, Darren Boehning

Research output: Contribution to journalArticle

33 Citations (Scopus)

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

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
Endoplasmic Reticulum
Tumors
Calcium
BRCA1 Protein
Apoptosis
Neoplasms
Proteins
Proto-Oncogenes
Cell death
Calcium Channels
Cell Death
Ligands
Lipids

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release. / Hedgepeth, Serena C.; Garcia, M. Iveth; Wagner, Larry E.; Rodriguez, Ana; Chintapalli, Sree V.; Snyder, Russell; Hankins, Gary; Henderson, Beric R.; Brodie, Kirsty M.; Yule, David I.; Van Rossum, Damian B.; Boehning, Darren.

In: Journal of Biological Chemistry, Vol. 290, No. 11, 13.03.2015, p. 7304-7313.

Research output: Contribution to journalArticle

Hedgepeth, SC, Garcia, MI, Wagner, LE, Rodriguez, A, Chintapalli, SV, Snyder, R, Hankins, G, Henderson, BR, Brodie, KM, Yule, DI, Van Rossum, DB & Boehning, D 2015, 'The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release', Journal of Biological Chemistry, vol. 290, no. 11, pp. 7304-7313. https://doi.org/10.1074/jbc.M114.611186
Hedgepeth, Serena C. ; Garcia, M. Iveth ; Wagner, Larry E. ; Rodriguez, Ana ; Chintapalli, Sree V. ; Snyder, Russell ; Hankins, Gary ; Henderson, Beric R. ; Brodie, Kirsty M. ; Yule, David I. ; Van Rossum, Damian B. ; Boehning, Darren. / The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 11. pp. 7304-7313.
@article{eeca3438f79e4c649a3d31257e01266d,
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.",
author = "Hedgepeth, {Serena C.} and Garcia, {M. Iveth} and Wagner, {Larry E.} and Ana Rodriguez and Chintapalli, {Sree V.} and Russell Snyder and Gary Hankins and Henderson, {Beric R.} and Brodie, {Kirsty M.} and Yule, {David I.} and {Van Rossum}, {Damian B.} and Darren Boehning",
year = "2015",
month = "3",
day = "13",
doi = "10.1074/jbc.M114.611186",
language = "English (US)",
volume = "290",
pages = "7304--7313",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "11",

}

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

AU - Chintapalli, Sree V.

AU - Snyder, Russell

AU - Hankins, Gary

AU - Henderson, Beric R.

AU - Brodie, Kirsty M.

AU - Yule, David I.

AU - Van Rossum, Damian B.

AU - Boehning, Darren

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.

UR - http://www.scopus.com/inward/record.url?scp=84924897990&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924897990&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.611186

DO - 10.1074/jbc.M114.611186

M3 - Article

VL - 290

SP - 7304

EP - 7313

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 11

ER -