Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression

M Wysk; D D Yang; H T Lu; R A Flavell; R J Davis

doi:10.1073/pnas.96.7.3763

Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression

Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3763-8. doi: 10.1073/pnas.96.7.3763.

Authors

M Wysk¹, D D Yang, H T Lu, R A Flavell, R J Davis

Affiliation

¹ Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Abstract

The p38 mitogen-activated protein kinase is activated by treatment of cells with cytokines and by exposure to environmental stress. The effects of these stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6. We have examined the function of the p38 MAP kinase signaling pathway by investigating the effect of targeted disruption of the Mkk3 gene. Here we report that Mkk3 gene disruption caused a selective defect in the response of fibroblasts to the proinflammatory cytokine tumor necrosis factor, including reduced p38 MAP kinase activation and cytokine expression. These data demonstrate that the MKK3 protein kinase is a critical component of a tumor necrosis factor-stimulated signaling pathway that causes increased expression of inflammatory cytokines.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Cells, Cultured
Cytokines / genetics*
Fibroblasts / cytology
Fibroblasts / physiology
Gene Expression Regulation* / drug effects
Gene Expression Regulation* / radiation effects
Interleukin-1 / genetics
Interleukin-6 / genetics
Intracellular Signaling Peptides and Proteins
JNK Mitogen-Activated Protein Kinases
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases*
Molecular Sequence Data
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism*
Restriction Mapping
Sorbitol / pharmacology
Tumor Necrosis Factor-alpha / physiology*
Ultraviolet Rays
p38 Mitogen-Activated Protein Kinases

Substances

Cytokines
Interleukin-1
Interleukin-6
Intracellular Signaling Peptides and Proteins
Tumor Necrosis Factor-alpha
Sorbitol
MAP-kinase-activated kinase 3
Protein Serine-Threonine Kinases
Calcium-Calmodulin-Dependent Protein Kinases
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases