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Molecular and Cellular Biology, February 2001, p. 1249-1259, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1249-1259.2001

Gadd153 Sensitizes Cells to Endoplasmic Reticulum Stress by Down-Regulating Bcl2 and Perturbing the Cellular Redox State

Karen D. McCullough,1 Jennifer L. Martindale,1 Lars-Oliver Klotz,1 Tak-Yee Aw,2,dagger and Nikki J. Holbrook1,*

Cell Stress and Aging Section, Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825,1 and Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Louisiana State University, Shreveport, Louisiana 711302

Received 15 May 2000/Returned for modification 21 June 2000/Accepted 14 November 2000

gadd153, also known as chop, is a highly stress-inducible gene that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). Although all reported types of ER stress induce expression of Gadd153, its role in the stress response has remained largely undefined. Several studies have correlated Gadd153 expression with cell death, but a mechanistic link between Gadd153 and apoptosis has never been demonstrated. To address this issue we employed a cell model system in which Gadd153 is constitutively overexpressed, as well as two cell lines in which Gadd153 expression is conditional. In all cell lines, overexpression of Gadd153 sensitized cells to ER stress. Investigation of the mechanisms contributing to this effect revealed that elevated Gadd153 expression results in the down-regulation of Bcl2 expression, depletion of cellular glutathione, and exaggerated production of reactive oxygen species. Restoration of Bcl2 expression in Gadd153-overexpressing cells led to replenishment of glutathione and a reduction in levels of reactive oxygen species, and it protected cells from ER stress-induced cell death. We conclude that Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bcl2 and enhanced oxidant injury.

* Corresponding author. Mailing address: Laboratory of Biological Chemistry, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8446. Fax: (410) 558-8386. E-mail: nikki-holbrook{at}nih.gov.

dagger Present address: Institut fur Physiologische Chemie I, Heinrich-Heine-Universitat Dusseldorf, D-40225 Dusseldorf, Germany.

Molecular and Cellular Biology, February 2001, p. 1249-1259, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1249-1259.2001


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