In response to a variety of cell stresses, e.g. endoplasmic reticulum (ER) stress, expression of REDD1 (regulated in development and DNA damage responses) is transcriptionally upregulated. However, the mechanism through which ER stress acts to upregulate REDD1 expression is unknown. In the present study, REDD1 expression was found to be upregulated by ER stress in several cell lines. However, in MEF cells lacking the elF2 alpha kinase PERK, ER stress failed to upregulate REDD1 expression, demonstrating that phosphorylation of elF2 of. was necessary for the effect. Moreover, ER stress led to upregulated expression of the transcription factor ATF4, but in MEF cells lacking ATF4, REDD1 mRNA expression was not increased by ER stress. In contrast, exogenous expression of ATF4 was sufficient to induce REDD1 expression. Overall, the results Suggest that REDD1 expression is upregulated during ER stress through a mechanism involving activation of PERK, phosphorylation of elf2 alpha and increased ATF4 expression. (C) 2008 Elsevier Inc. All rights reserved.