Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption

Targeted disruption of the gene encoding MEK kinase 1 (MEKK1), a mitogen-ac tivated protein kinase (MAPK) kinase kinase, defined its function in the re gulation of MAPK pathways and cell survival. MEKK1(-/-) embryonic stem cell s from mice had Lost or altered responses of the c-Jun amino-terminal kinas e (INK) to microtubule disruption and cold stress but activated JNK normall y in response to heat shock, anisomycin, and ultraviolet irradiation. Activ ation of JNK was Lost and that of extracellular signal-regulated protein ki nase (ERK) was diminished in response to hyperosmolarity and serum factors in MEKK1(-/-) cells. Loss of MEKK1 expression resulted in a greater apoptot ic response of cells to hyperosmolarity and microtubule disruption. When ac tivated by specific stresses that alter cell shape and the cytoskeleton, ME KK1 Signals to protect cells from apoptosis.