BH3-only BIK Regulates BAX,BAK-dependent Release of Ca2+ from Endoplasmic Reticulum Stores and Mitochondrial Apoptosis during Stress-induced Cell Death

BIK, a pro-apoptotic BH3-only member of the BCL-2 family, targets the membrane of the endoplasmic reticulum (ER). It is induced in human cells in response to several stress stimuli, including genotoxic stress (radiation, doxorubicin) and overexpression of E1A or p53 but not by ER stress pathways res...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2005-06, Vol.280 (25), p.23829-23836
Main Authors: Mathai, Jaigi P., Germain, Marc, Shore, Gordon C.
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis Regulatory Proteins
Base Sequence
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Calcium - metabolism
Cell Line, Tumor
DNA Primers
Endoplasmic Reticulum - metabolism
Humans
Membrane Proteins - physiology
Mitochondria - metabolism
Mitochondrial Proteins
Mutagens - toxicity
Oncogenes
Oxidative Stress
Proto-Oncogene Proteins c-bcl-2 - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:BIK, a pro-apoptotic BH3-only member of the BCL-2 family, targets the membrane of the endoplasmic reticulum (ER). It is induced in human cells in response to several stress stimuli, including genotoxic stress (radiation, doxorubicin) and overexpression of E1A or p53 but not by ER stress pathways resulting from protein malfolding. BIK initiates an early release of Ca2+ from ER upstream of the activation of effector caspases. Release of the mobile ER Ca2+ stores in baby mouse kidney cells doubly deficient in BAX and BAK, on the other hand, is resistant to BIK but is sensitive to ectopic BAK. Over-expression of p53 stimulates recruitment of BAK to the ER, and both its recruitment and assembly into higher order structures is inhibited by BIK small interfering RNA. Employing small interfering RNA knockdowns, we also demonstrated that release of ER Ca2+ and mitochondrial apoptosis in human epithelial cells requires BIK and that a Ca2+-regulated target, the dynamin-related GTPase DRP1, is involved in p53-induced mitochondrial fission and release of cytochrome c to the cytosol. Endogenous cellular BIK, therefore, regulates a BAX,BAK-dependent ER pathway that contributes to mitochondrial apoptosis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M500800200