GSBS Student Publications


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

UMMS Affiliation

Graduate School of Biomedical Sciences; Program in Molecular Medicine



Document Type


Medical Subject Headings

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


Life Sciences | Medicine and Health Sciences


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.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3763-8.

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID