PMID- 10570180
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 24
DP  - 1999 Nov 23
TI  - Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated 
      protein kinase whereas IFN-gamma uses a different signaling pathway.
PG  - 13956-61
AB  - STAT1 is an essential transcription factor for macrophage activation by IFN-gamma
      and requires phosphorylation of the C-terminal Ser727 for transcriptional
      activity. In macrophages, Ser727 phosphorylation in response to bacterial
      lipopolysaccharide (LPS), UV irradiation, or TNF-alpha occurred through a
      signaling path sensitive to the p38 mitogen-activated protein kinase (p38 MAPK)
      inhibitor SB203580 whereas IFN-gamma-mediated Ser727 phosphorylation was not
      inhibited by the drug. Consistently, SB203580 did not affect IFN-gamma-mediated, 
      Stat1-dependent transcription but inhibited its enhancement by LPS. Furthermore, 
      LPS, UV irradiation, and TNF-alpha caused activation of p38 MAPK whereas
      IFN-gamma did not. An essential role for p38 MAPK activity in STAT1 Ser727
      phosphorylation was confirmed by using cells expressing an SB203580-resistant p38
      MAPK. In such cells, STAT1 Ser727 phosphorylation in response to UV irradiation
      was found to be SB203580 insensitive. Targeted disruption of the mapkap-k2 gene, 
      encoding a kinase downstream of p38 MAPK with a key role in LPS-stimulated
      TNF-alpha production and stress-induced heat shock protein 25 phosphorylation,
      was without a significant effect on UV-mediated Ser727 phosphorylation. The
      recombinant Stat1 C terminus was phosphorylated in vitro by p38MAPKalpha and beta
      but not by MAPK-activated protein kinase 2. Janus kinase 2 activity, previously
      reported to be required for IFN-gamma-mediated Ser727 phosphorylation, was not
      needed for LPS-mediated Ser727 phosphorylation, and activation of Janus kinase 2 
      did not cause the appearance of STAT1 Ser727 kinase activity. Our data suggest
      that STAT1 is phosphorylated at Ser727 by a stress-activated signaling pathway
      either through p38 MAPK directly or through an unidentified kinase downstream of 
      p38MAPK.
FAU - Kovarik, P
AU  - Kovarik P
AD  - Vienna Biocenter, Institute of Microbiology and Genetics, Dr. Bohr-Gasse 9,
      A-1030 Vienna, Austria.
FAU - Stoiber, D
AU  - Stoiber D
FAU - Eyers, P A
AU  - Eyers PA
FAU - Menghini, R
AU  - Menghini R
FAU - Neininger, A
AU  - Neininger A
FAU - Gaestel, M
AU  - Gaestel M
FAU - Cohen, P
AU  - Cohen P
FAU - Decker, T
AU  - Decker T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
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 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 452VLY9402 (Serine)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.1.- (MAP-kinase-activated kinase 2)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Transformed
MH  - DNA-Binding Proteins/*metabolism
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Interferon-gamma/*metabolism
MH  - Intracellular Signaling Peptides and Proteins
MH  - Janus Kinase 2
MH  - Lipopolysaccharides/pharmacology
MH  - *MAP Kinase Signaling System
MH  - Macrophages/cytology/drug effects/metabolism/radiation effects
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Protein-Tyrosine Kinases/metabolism
MH  - *Proto-Oncogene Proteins
MH  - Pyridines/pharmacology
MH  - Rabbits
MH  - Recombinant Fusion Proteins/metabolism
MH  - STAT1 Transcription Factor
MH  - Serine/*metabolism
MH  - Trans-Activators/*metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/immunology/pharmacology
MH  - Ultraviolet Rays
MH  - p38 Mitogen-Activated Protein Kinases
PMC - PMC24172
EDAT- 1999/11/26 00:00
MHDA- 1999/11/26 00:01
CRDT- 1999/11/26 00:00
PHST- 1999/11/26 00:00 [pubmed]
PHST- 1999/11/26 00:01 [medline]
PHST- 1999/11/26 00:00 [entrez]
AID - 10.1073/pnas.96.24.13956 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13956-61. doi:
      10.1073/pnas.96.24.13956.