PMID- 11106749
OWN - NLM
STAT- MEDLINE
DCOM- 20020122
LR  - 20220410
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 6
IP  - 5
DP  - 2000 Nov
TI  - Regulated translation initiation controls stress-induced gene expression in 
      mammalian cells.
PG  - 1099-108
AB  - Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation 
      factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate 
      protein synthesis. Phenotypic analysis of targeted mutations in murine cells 
      reveals a novel role for eIF2alpha kinases in regulating gene expression in the 
      unfolded protein response (UPR) and in amino acid starved cells. When activated 
      by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and 
      GCN2 repress translation of most mRNAs but selectively increase translation of 
      Activating Transcription Factor 4 (ATF4), resulting in the induction of the 
      downstream gene CHOP (GADD153). This is the first example of a mammalian 
      signaling pathway homologous to the well studied yeast general control response 
      in which eIF2alpha phosphorylation activates genes involved in amino acid 
      biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene 
      expression in response to diverse stress signals.
FAU - Harding, H P
AU  - Harding HP
AD  - Skirball Institute of Biomolecular Medicine The Department of Medicine, Kaplan 
      Cancer Center New York University School of Medicine, New York, NY 10016, USA.
FAU - Novoa, I
AU  - Novoa I
FAU - Zhang, Y
AU  - Zhang Y
FAU - Zeng, H
AU  - Zeng H
FAU - Wek, R
AU  - Wek R
FAU - Schapira, M
AU  - Schapira M
FAU - Ron, D
AU  - Ron D
LA  - eng
GR  - DK47119/DK/NIDDK NIH HHS/United States
GR  - ES08681/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Amino Acids)
RN  - 0 (Atf4 protein, rat)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Ddit3 protein, mouse)
RN  - 0 (Ddit3 protein, rat)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Eif2ak4 protein, mouse)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Activating Transcription Factor 4
MH  - Amino Acids/biosynthesis/*deficiency/genetics
MH  - Animals
MH  - CCAAT-Enhancer-Binding Proteins/genetics
MH  - Carrier Proteins/metabolism
MH  - Cell Line
MH  - Cricetinae
MH  - Endoplasmic Reticulum/metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Eukaryotic Initiation Factor-2/chemistry/metabolism
MH  - *Gene Expression Regulation
MH  - *Heat-Shock Proteins
MH  - Mammals/*genetics
MH  - Mice
MH  - Molecular Chaperones/metabolism
MH  - Mutation/genetics
MH  - *Peptide Chain Initiation, Translational
MH  - Phosphorylation
MH  - Protein Denaturation
MH  - *Protein Folding
MH  - Protein Kinases/genetics/metabolism
MH  - Protein Serine-Threonine Kinases
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Ribosomes/metabolism
MH  - Signal Transduction
MH  - Transcription Factor CHOP
MH  - Transcription Factors/biosynthesis/genetics
MH  - eIF-2 Kinase/genetics/*metabolism
EDAT- 2000/12/07 00:00
MHDA- 2002/01/23 10:01
CRDT- 2000/12/07 00:00
PHST- 2000/12/07 00:00 [pubmed]
PHST- 2002/01/23 10:01 [medline]
PHST- 2000/12/07 00:00 [entrez]
AID - S1097-2765(00)00108-8 [pii]
AID - 10.1016/s1097-2765(00)00108-8 [doi]
PST - ppublish
SO  - Mol Cell. 2000 Nov;6(5):1099-108. doi: 10.1016/s1097-2765(00)00108-8.