When homeostasis in the endoplasmic reticulum (ER) is disrupted, a stress signal is transduced to the nucleus to turn on the expression of numerous genes including gadd153, a leucine zipper transcription factor. Gadd153 expression is also thought to signal the onset of apoptosis. McCullough et al. report that overexpression of Gadd153 sensitizes cells to ER stress-inducing agents, resulting in enhanced cell death and caused decreased expression of the anti-apoptotic protein Bcl2. The authors speculate that this might occur through negative regulation of another transcription factor. Gadd153 overexpression also reduced amounts of cellular glutathione, a molecule that not only maintains protein integrity through regulation of cellular redox states, but also scavenges damaging reactive oxygen species (ROS). The authors speculate that Gadd153 may regulate the synthesis of cellular glutathione and may provide a mechanistic link between stress in the ER and cell death.
K. D. McCullough, J. L. Martindale, L.-O. Klotz, T.-Y. Aw, N. J. Holbrook, Gadd153 sensitizes cells to endoplsmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. 21: 1249-1259 (2001). [Abstract] [Full Text]