PMID- 18768473
OWN - NLM
STAT- MEDLINE
DCOM- 20081223
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 45
DP  - 2008 Nov 7
TI  - Hypoxic reactive oxygen species regulate the integrated stress response and cell 
      survival.
PG  - 31153-62
LID - 10.1074/jbc.M805056200 [doi]
AB  - Under hypoxic conditions, cells suppress energy-intensive mRNA translation by 
      modulating the mammalian target of rapamycin (mTOR) and pancreatic eIF2alpha 
      kinase (PERK) pathways. Much is known about hypoxic inhibition of mTOR activity; 
      however, the cellular processes activating PERK remain unclear. Since hypoxia is 
      known to increase intracellular reactive oxygen species (ROS), we hypothesized 
      that hypoxic ROS regulate mTOR and PERK to control mRNA translation and cell 
      survival. Our data indicate that although exogenous ROS inhibit mTOR, eIF2alpha, 
      and eEF2, mTOR and eEF2 were largely refractory to ROS generated under moderate 
      hypoxia (0.5% O(2)). In direct contrast, the PERK/eIF2alpha/ATF4 integrated 
      stress response (ISR) was activated by hypoxic ROS and contributed to global 
      protein synthesis inhibition and adaptive ATF4-mediated gene expression. The ISR 
      as well as exogenous growth factors were critical for cell viability during 
      extended hypoxia, since ISR inhibition decreased the viability of cells deprived 
      of O(2) and growth factors. Collectively, our data support an important role for 
      ROS in hypoxic cell survival. Under conditions of moderate hypoxia, ROS induce 
      the ISR, thereby promoting energy and redox homeostasis and enhancing cellular 
      survival.
FAU - Liu, Liping
AU  - Liu L
AD  - Howard Hughes Medical Institute, USA.
FAU - Wise, David R
AU  - Wise DR
FAU - Diehl, J Alan
AU  - Diehl JA
FAU - Simon, M Celeste
AU  - Simon MC
LA  - eng
GR  - P01 CA104838/CA/NCI NIH HHS/United States
GR  - P01 CA 104838/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080903
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Atf4 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Peptide Elongation Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Activating Transcription Factor 4/metabolism
MH  - Animals
MH  - Cell Hypoxia/physiology
MH  - Cell Survival
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - *Gene Expression Regulation
MH  - Mice
MH  - Peptide Elongation Factor 2/metabolism
MH  - *Protein Biosynthesis
MH  - Protein Kinases/metabolism
MH  - Reactive Oxygen Species/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - eIF-2 Kinase/metabolism
PMC - PMC2576535
EDAT- 2008/09/05 09:00
MHDA- 2008/12/24 09:00
PMCR- 2008/11/07
CRDT- 2008/09/05 09:00
PHST- 2008/09/05 09:00 [pubmed]
PHST- 2008/12/24 09:00 [medline]
PHST- 2008/09/05 09:00 [entrez]
PHST- 2008/11/07 00:00 [pmc-release]
AID - S0021-9258(20)64692-0 [pii]
AID - 31153 [pii]
AID - 10.1074/jbc.M805056200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Nov 7;283(45):31153-62. doi: 10.1074/jbc.M805056200. Epub 2008 
      Sep 3.