Activating transcription factor 4 and CCAAT/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress.
Regulation of mRNA translation in mammalian cells involves the coordinated control of mammalian target of rapamycin (mTOR) signaling. At present, limited information is available on the potential relevance of mTOR regulation, although translation inhibition during oxidative and endoplasmic reticulum (ER) stress is clearly important. In this study, we show that activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-beta (C/EBP-beta) negatively regulate mTOR via Redd1 expression in response to oxidative and ER stress. Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression. In our experiment, overexpression of ATF4 was associated with reduced mTOR activity via Redd1 expression, whereas suppression of ATF4 levels with small interfering RNA led to the recovery of decreased mTOR activity mediated by downregulation of Redd1 during oxidative and ER stress. We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress.
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, Republic of Korea.
Hyeon-Ok
HO
Jin
Sung-Keum
SK
Seo
Sang-Hyeok
SH
Woo
Eun-Sung
ES
Kim
Hyung-Chahn
HC
Lee
Doo-Hyun
DH
Yoo
Sungkwan
S
An
Tae-Boo
TB
Choe
Su-Jae
SJ
Lee
Seok-Il
SI
Hong
Chang-Hun
CH
Rhee
Jong-Il
JI
Kim
In-Chul
IC
Park
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D004721:Endoplasmic Reticulum; D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018384:Oxidative Stress; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
C497109:ATF4 protein, human; D022782:CCAAT-Enhancer-Binding Protein-beta; C469991:DDIT4 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D006861:Hydrogen Peroxide; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus