PMID- 9177222
OWN - NLM
STAT- MEDLINE
DCOM- 19970710
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 94
IP  - 12
DP  - 1997 Jun 10
TI  - Mast cell tumor necrosis factor alpha production is regulated by MEK kinases.
PG  - 6358-63
AB  - Mast cells synthesize and secrete specific cytokines and chemokines which play an 
      important role in allergic inflammation. Aggregation of the high-affinity Fc 
      receptor (FcepsilonRI) for immunoglobulin E (IgE) in MC/9 mouse mast cells 
      stimulates the synthesis and secretion of tumor necrosis factor alpha 
      (TNF-alpha). FcepsilonRI aggregation activates several sequential protein kinase 
      pathways, leading to increased activity of extracellular signal-regulated kinases 
      (ERKs), c-Jun amino-terminal kinases (JNKs), and the p38 mitogen-activated 
      protein (MAP) kinase. Inhibition of ERKs with the compound PD 098059 had little 
      effect on FcepsilonRI-stimulated TNF-alpha production. Aggregation of FcepsilonRI 
      stimulated MEK kinase 1 (MEKK1) activity, which activates JNK kinase (JNKK), the 
      kinase that phosphorylates and activates JNKs. Expression of activated MEKK1 
      (DeltaMEKK1) in MC/9 cells strongly stimulated JNK activity but only weakly 
      stimulated p38 activity, and it induced a large activation of TNF-alpha 
      promoter-regulated luciferase gene expression. Inhibitory mutant JNK2 expressed 
      in MC/9 cells significantly blunted FcepsilonRI stimulation of TNF-alpha 
      promoter-driven luciferase expression. Wortmannin, an inhibitor of 
      phosphatidylinositol 3-kinase, diminished FcepsilonRI-mediated TNF-alpha 
      synthesis, significantly blunted JNK activation and TNF-alpha promoter-driven 
      luciferase expression, and only weakly inhibited p38 kinase activation. 
      Inhibition of NFkappaB activation resulting from DeltaMEKK1 expression or 
      FcepsilonRI stimulation did not affect TNF-alpha promoter-driven luciferase 
      expression. Our findings define a MEKK-regulated JNK pathway activated by 
      FcepsilonRI that regulates TNF-alpha production in mast cells.
FAU - Ishizuka, T
AU  - Ishizuka T
AD  - Division of Basic Sciences, Department of Pediatrics, and Program in Molecular 
      Signal Transduction, National Jewish Medical and Research Center, 1400 Jackson 
      Street, Denver, CO 80206, USA.
FAU - Terada, N
AU  - Terada N
FAU - Gerwins, P
AU  - Gerwins P
FAU - Hamelmann, E
AU  - Hamelmann E
FAU - Oshiba, A
AU  - Oshiba A
FAU - Fanger, G R
AU  - Fanger GR
FAU - Johnson, G L
AU  - Johnson GL
FAU - Gelfand, E W
AU  - Gelfand EW
LA  - eng
GR  - P01 HL036577/HL/NHLBI NIH HHS/United States
GR  - R01 DK037871/DK/NIDDK NIH HHS/United States
GR  - AI HL-36577/AI/NIAID NIH HHS/United States
GR  - DK-37871/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Androstadienes)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Thiazoles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9R6QDF1UO7 (6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (Map3k1 protein, mouse)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cell Line
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Glutathione Transferase
MH  - Imidazoles/pharmacology
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Kinetics
MH  - Luciferases/biosynthesis
MH  - *MAP Kinase Kinase Kinase 1
MH  - Mast Cells/*immunology
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1
MH  - *Mitogen-Activated Protein Kinases
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Thiazoles/pharmacology
MH  - Transcription, Genetic/drug effects
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
MH  - Wortmannin
PMC - PMC21054
EDAT- 1997/06/10 00:00
MHDA- 1997/06/10 00:01
PMCR- 1997/12/10
CRDT- 1997/06/10 00:00
PHST- 1997/06/10 00:00 [pubmed]
PHST- 1997/06/10 00:01 [medline]
PHST- 1997/06/10 00:00 [entrez]
PHST- 1997/12/10 00:00 [pmc-release]
AID - 10.1073/pnas.94.12.6358 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6358-63. doi: 
      10.1073/pnas.94.12.6358.