Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death

Nancy Lassignal Johnson, Anne M. Gardner, Katrina M. Diener, Carol A. Lange-Carter, Janice Gleavy, Matthew B. Jarpe, Audrey Minden, Michael Karin, Leonard I. Zon, Gary L. Johnson

Research output: Contribution to journalArticlepeer-review

322 Scopus citations

Abstract

Mitogen-activated/extracellular response kinase kinase (MEK) kinase (MEKK) is a serine-threonine kinase that regulates sequential protein phosphorylation pathways, leading to the activation of mitogen-activated protein kinases (MAPK), including members of the Jun kinase (JNK)/stress- activated protein kinase (SAPK) family. In Swiss 3T3 and REF52 fibroblasts, activated MEKK induces cell death involving cytoplasmic shrinkage, nuclear condensation, and DNA fragmentation characteristic of apoptosis. Expression of activated MEKK enhanced the apoptotic response to ultraviolet irradiation, indicating that MEKK-regulated pathways sensitize cells to apoptotic stimuli. Inducible expression of activated MEKK stimulated the transactivation of c- Myc and Elk-1. Activated Raf, the serine-threonine protein kinase that activates the ERK members of the MAPK family, stimulated Elk-1 transactivation but not c-Myc; expression of activated Raf does not induce any of the cellular changes associated with MEKK-mediated cell death. Thus, MEKK selectively regulates signal transduction pathways that contribute to the apoptotic response.

Original languageEnglish (US)
Pages (from-to)3229-3237
Number of pages9
JournalJournal of Biological Chemistry
Volume271
Issue number6
DOIs
StatePublished - Feb 9 1996
Externally publishedYes

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