Changes in Endoplasmic Reticulum Luminal Environment Affect Cell Sensitivity to Apoptosis

doi:10.1083/jcb.150.4.731

Published online 21 August 2000. doi:10.1083/jcb.150.4.731

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© The Rockefeller University Press, 0021-9525/2000/8/731/ $5.00
The Journal of Cell Biology, Volume 150, Number 4, August 21, 2000 731-740

Original Article

Changes in Endoplasmic Reticulum Luminal Environment Affect Cell Sensitivity to Apoptosis

Kimitoshi Nakamura^a,b, Ella Bossy-Wetzel^c, Kimberly Burns^a,b, Marc P. Fadel^d, Mira Lozyk^d, Ing Swie Goping^b, Michal Opas^d, R. Chris Bleackley^b, Douglas R. Green^c, and Marek Michalak^a
^a Canadian Institutes of Health Research Group in Molecular Biology of Membrane Proteins, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7,
^b Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7,
^c La Jolla Institute for Allergy and Immunology, San Diego, California 92121,
^d Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Correspondence to: Marek Michalak, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Tel:(780) 492-2256 Fax:(780) 492-0886 E-mail:marek.michalak{at}ualberta.ca.

To test the role of ER luminal environment in apoptosis, wegenerated HeLa cell lines inducible with respect to calreticulinand calnexin and investigated their sensitivity to drug-dependentapoptosis. Overexpression of calreticulin, an ER luminal protein,resulted in an increased sensitivity of the cells to both thapsigargin-and staurosporine-induced apoptosis. This correlated with anincreased release of cytochrome c from the mitochondria. Overexpressionof calnexin, an integral ER membrane protein, had no significanteffect on drug-induced apoptosis. In contrast, calreticulin-deficientcells were significantly resistant to apoptosis and this resistancecorrelated with a decreased release of cytochrome c from mitochondriaand low levels of caspase 3 activity. This work indicates thatchanges in the lumen of the ER amplify the release of cytochromec from mitochondria, and increase caspase activity, during drug-inducedapoptosis. There may be communication between the ER and mitochondria,which may involve Ca²⁺ and play an important role in conferringcell sensitivity to apoptosis. Apoptosis may depend on boththe presence of external apoptosis-activating signals, and,as shown in this study, on an internal factor represented bythe ER.

Key Words: apoptosis, calreticulin, endoplasmic reticulum, calcium-bindingprotein

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