SIGNAL-TRANSDUCTION PATHWAYS REGULATED BY MITOGEN-ACTIVATED EXTRACELLULAR RESPONSE KINASE KINASE KINASE INDUCE CELL-DEATH

Mitogen-activated/extracellular response kinase kinase (MEK) kinase (M EKK) is a serine-threonine kinase that regulates sequential protein ph osphorylation pathways, leading to the activation of mitogen-activated protein kinases (MAPK), including members of the Jun kinase (JNK)/str ess-activated protein kinase (SAPK) family. In Swiss 3T3 and REF52 fib roblasts, activated MEKK induces cell death involving cytoplasmic shri nkage, nuclear condensation, and DNA fragmentation characteristic of a poptosis. Expression of activated MEKK enhanced the apoptotic response to ultraviolet irradiation, indicating that MEKK-regulated pathways s ensitize cells to apoptotic stimuli. Inducible expression of activated MEKK stimulated the transactivation of c-Myc and Elk-1. Activated Raf , the serine-threonine pro tein kinase that activates the ERK members of the MAPK family, stimulated Elk-1 transactivation but not c-Myc; ex pression of activated Raf does not induce any of the cellular changes associated with MEKK-mediated cell death, Thus, MEKK selectively regul ates signal transduction pathways that contribute to the apoptotic res ponse.