Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bc12 and perturbing the cellular redox state

gadd153, also known as chop, is a highly stress-inducible gene that is robu stly expressed following disruption of homeostasis in the endoplasmic retic ulum (ER) (so-called ER stress). Although all reported types of ER stress i nduce expression of Gadd153, its role in the stress response has remained l argely undefined. Several studies have correlated Gadd153 expression with c ell death, but a mechanistic link between Gadd153 and apoptosis has never b een 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 resul ts in the down-regulation of Bc12 expression, depletion of cellular glutath ione, and exaggerated production of reactive oxygen species. Restoration of Bc12 expression in Gadd153-overexpressing cells led to replenishment of gl utathione and a reduction in levels of reactive oxygen species, and it prot ected cells from ER stress-induced cell death. We conclude that Gadd153 sen sitizes cells to ER stress through mechanisms that involve down-regulation of Bc12 and enhanced oxidant injury.