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The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide‐induced apoptosis: significance for the molecular mechanism of Bcl‐2 action

The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide‐induced... The mechanism of action of the anti‐apoptotic oncogene Bcl‐2 is still largely obscure. We have recently shown that the overexpression of Bcl‐2 in HeLa cells reduces the Ca2+ concentration in the endoplasmic reticulum ([Ca2+]er) by increasing the passive Ca2+ leak from the organelle. To investigate whether this Ca2+ depletion is part of the mechanism of action of Bcl‐2, we mimicked the Bcl‐2 effect on [Ca2+]er by different pharmacological and molecular approaches. All conditions that lowered [Ca2+]er protected HeLa cells from ceramide, a Bcl‐2‐sensitive apoptotic stimulus, while treatments that increased [Ca2+]er had the opposite effect. Surprisingly, ceramide itself caused the release of Ca2+ from the endoplasmic reticulum and thus [Ca2+] increased both in the cytosol and in the mitochondrial matrix, paralleled by marked alterations in mitochondria morphology. The reduction of [Ca2+]er levels, as well as the buffering of cytoplasmic [Ca2+] changes, prevented mitochondrial damage and protected cells from apoptosis. It is therefore concluded that the Bcl‐2‐dependent reduction of [Ca2+]er is an important component of the anti‐apoptotic program controlled by this oncogene. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide‐induced apoptosis: significance for the molecular mechanism of Bcl‐2 action

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References (77)

Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1093/emboj/20.11.2690
pmid
11387204
Publisher site
See Article on Publisher Site

Abstract

The mechanism of action of the anti‐apoptotic oncogene Bcl‐2 is still largely obscure. We have recently shown that the overexpression of Bcl‐2 in HeLa cells reduces the Ca2+ concentration in the endoplasmic reticulum ([Ca2+]er) by increasing the passive Ca2+ leak from the organelle. To investigate whether this Ca2+ depletion is part of the mechanism of action of Bcl‐2, we mimicked the Bcl‐2 effect on [Ca2+]er by different pharmacological and molecular approaches. All conditions that lowered [Ca2+]er protected HeLa cells from ceramide, a Bcl‐2‐sensitive apoptotic stimulus, while treatments that increased [Ca2+]er had the opposite effect. Surprisingly, ceramide itself caused the release of Ca2+ from the endoplasmic reticulum and thus [Ca2+] increased both in the cytosol and in the mitochondrial matrix, paralleled by marked alterations in mitochondria morphology. The reduction of [Ca2+]er levels, as well as the buffering of cytoplasmic [Ca2+] changes, prevented mitochondrial damage and protected cells from apoptosis. It is therefore concluded that the Bcl‐2‐dependent reduction of [Ca2+]er is an important component of the anti‐apoptotic program controlled by this oncogene.

Journal

The EMBO Journal – Wiley

Published: Jan 1, 2001

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