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J. Biol. Chem., Vol. 275, Issue 36, 27858-27864, September 8, 2000
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From the University of Iowa College of Medicine and the Iowa City
Veterans Administration Medical Center, Iowa City, Iowa 52242
Endotoxin-induced cytokine gene expression is
regulated, in part, by NF-
A Constitutive Active MEK
ERK Pathway Negatively Regulates
NF-
B-dependent Gene Expression by Modulating
TATA-binding Protein Phosphorylation*
and
B. We have shown that both the ERK and p38
mitogen-activated protein (MAP) kinases are necessary for cytokine gene
transcription and that the p38 MAP kinase is required for
NF-B-driven transcription, so we hypothesized that the MEK 
ERK
pathway regulated NF-B-driven transcription as well. We found that a
constitutive active MEK ERK pathway inhibited NF-B-driven
transcription. In addition, both PD 98059 and a dominant negative ERK2
augmented NF-B-driven transcription; however, neither PD 98059 nor
MEK1 altered NF-B activation at any level. The constitutive active
MEK ERK pathway inhibited the phosphorylation of TBP, which is
necessary for both interaction with RelA and binding to the TATA box.
Due to the fact that we have shown that the p38 MAP kinase modulates
TBP activation, we evaluated the effect of the constitutive active MEK
ERK pathway on p38 MAP kinase activity. We found that the MEK ERK pathway negatively regulates NF-B-driven transcription, in part,
by inhibiting p38 MAP kinase activity. Thus, the ERK and p38 MAP
kinases have differential effects on NF-B-driven transcription.
*
This work was supported by National Institutes of Health
Grants HL03860 (to A. B. C.), Grant HL60316 (to G. W. H.), and
Grant AI35018 (to G. W. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of Pulmonary
and Critical Care Medicine, C33 GH, University of Iowa Hospital and
Clinics, 200 Hawkins Dr., Iowa City, IA 52242. Tel.: 319-353-7852; Fax:
319-356-8101; E-mail: aaron-carter@uiowa.edu.
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