TY - JOUR
T1 - ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression
AU - Whitney, Michael L.
AU - Jefferson, Leonard S.
AU - Kimball, Scot R.
N1 - Funding Information:
The authors would like to thank Holly Lacko for performing the qRT-PCR assays described herein. The studies described in this manuscript were supported by a grant from the National Institutes of Health (DK13499).
PY - 2009/2/6
Y1 - 2009/2/6
N2 - 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 eIF2α kinase PERK, ER stress failed to upregulate REDD1 expression, demonstrating that phosphorylation of eIF2α 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 eIF2α, and increased ATF4 expression.
AB - 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 eIF2α kinase PERK, ER stress failed to upregulate REDD1 expression, demonstrating that phosphorylation of eIF2α 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 eIF2α, and increased ATF4 expression.
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U2 - 10.1016/j.bbrc.2008.12.079
DO - 10.1016/j.bbrc.2008.12.079
M3 - Article
C2 - 19114033
AN - SCOPUS:58149524838
SN - 0006-291X
VL - 379
SP - 451
EP - 455
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -