It has been demonstrated that depletion of cellular thiols in lymphoma cells leads to an increased susceptibility of the cells to radiation-induced apoptosis. To elucidate the responsible mechanisms we used cDNA array hybridization to screen for differences in gene expression induced by thiol depletion. Among other genes we found the transcription factor Gadd153 to be upregulated after exposing the cells to cystine/methionine free culture medium. To study the functional consequences of this upregulation, cells constitutively expressing high levels of Gadd153 were generated by transfection. We found that overexpression of Gadd153 slightly reduced the amount of radiation-induced apoptosis in cells kept in normal medium but very significantly reduced apoptosis (from 55% to 18%) in cells which were treated with cystine/methionine free culture medium. The observed protective effect of Gadd153 against radiation-induced apoptosis in thiol depleted lymphoma cells argues for an anti-apoptotic function of Gadd153 after perturbation of the cellular redox state. (C) 2003 Elsevier Inc. All rights reserved.