PMID- 12807916
OWN - NLM
STAT- MEDLINE
DCOM- 20031007
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 36
DP  - 2003 Sep 5
TI  - Stimulation of signal transducer and activator of transcription-1 
      (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma 
      is regulated by mammalian target of rapamycin.
PG  - 33637-44
AB  - Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) 
      regulate cell growth, protein synthesis, and apoptosis in response to nutrients 
      and mitogens. As an important source of nitric oxide during inflammation, human 
      inducible nitric oxide synthase also plays a role in the regulation of 
      cytokine-driven cell proliferation and apoptosis. The role of mTOR and PI3K in 
      the activation of human inducible nitric oxide synthase transcription by 
      cytokines and lipopolysaccharide (LPS) was investigated in lung epithelial 
      adenocarcinoma (A549) cells. LY294002, a dual mTOR and PI3K inhibitor, blocked 
      human inducible nitric oxide synthase (hiNOS) promoter activation and mRNA 
      induction by cytokines and LPS in a PI3K-independent fashion. On gene expression 
      analysis, LY294002 selectively blocked the induction of a subset of 14 
      LPS/interferon-gamma (IFN-gamma)-induced genes, previously characterized as 
      signal transducer and activator of transcription-1 (STAT1)-dependent. LY294002, 
      but not wortmannin, inhibited LPS/IFN-gamma-dependent STAT1 phosphorylation at 
      Ser-727 and STAT1 activity. Consistent with dual inhibition of mTOR and PI3K by 
      LY294002, dominant-negative mTOR, anti-mTOR small interfering RNA, or rapamycin 
      each inhibited phosphorylation of STAT1 only in the presence of wortmannin. 
      LPS/IFN-gamma led to the formation of a macromolecular complex containing mTOR, 
      STAT1, as well as protein kinase C delta, a known STAT1alpha kinase. Thus, LPS 
      and IFN-gamma activate the PI3K and mTOR pathways, which converge to regulate 
      STAT1-dependent transcription of pro-apoptotic and pro-inflammatory genes in a 
      rapamycin-insensitive manner.
FAU - Kristof, Arnold S
AU  - Kristof AS
AD  - Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood 
      Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 
      kristofa@nih.gov
FAU - Marks-Konczalik, Joanna
AU  - Marks-Konczalik J
FAU - Billings, Eric
AU  - Billings E
FAU - Moss, Joel
AU  - Moss J
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030614
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Cytokines)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Morpholines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 0 (Trans-Activators)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 452VLY9402 (Serine)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (PRKCD protein, human)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Apoptosis
MH  - Blotting, Northern
MH  - Cell Division
MH  - Chromones/pharmacology
MH  - Cytokines/metabolism
MH  - DNA-Binding Proteins/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Genes, Dominant
MH  - Humans
MH  - Inflammation
MH  - Interferon-gamma/*metabolism
MH  - Lipopolysaccharides/*metabolism
MH  - Models, Biological
MH  - Morpholines/pharmacology
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Precipitin Tests
MH  - Promoter Regions, Genetic
MH  - Protein Kinase C/metabolism
MH  - Protein Kinase C-delta
MH  - Protein Kinases/*metabolism
MH  - RNA, Small Interfering/metabolism
MH  - STAT1 Transcription Factor
MH  - Serine/chemistry
MH  - TOR Serine-Threonine Kinases
MH  - Trans-Activators/*metabolism
MH  - *Transcription, Genetic
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Wortmannin
EDAT- 2003/06/17 05:00
MHDA- 2003/10/08 05:00
CRDT- 2003/06/17 05:00
PHST- 2003/06/17 05:00 [pubmed]
PHST- 2003/10/08 05:00 [medline]
PHST- 2003/06/17 05:00 [entrez]
AID - S0021-9258(20)83666-7 [pii]
AID - 10.1074/jbc.M301053200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Sep 5;278(36):33637-44. doi: 10.1074/jbc.M301053200. Epub 2003 
      Jun 14.