SEK1 DEFICIENCY REVEALS MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE CROSSREGULATION AND LEADS TO ABNORMAL HEPATOGENESIS

SEK1 (MKK4/JNKK) is a mitogen-activated protein kinase activator that has been shown to participate in vitro in two stress-activated cascade s terminating with the SAPK and p38 kinases. To define the role of SEK 1 in vivo, we studied stress-induced signaling in SEK1(-/-) embryonic stem and fibroblast cells and evaluated the phenotype of SEK1(-/-) mou se embryos during development. Studies of SEK1(-/-) embryonic stem cel ls demonstrated defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase. In contrast, SEK1(-/-) fibroblasts exhibited defects in both SAPK and p38 phosphorylation, demonstrating that crosstalk exists between the stress-activated cascades. Tumor nec rosis factor LY and interleukin 1 stimulation of both stress-activated cascades are severely affected in the SEK1(-/-) fibroblast cells. SEK 1 deficiency leads to embryonic lethality after embryonic day 12.5 and is associated with abnormal liver development, This phenotype is simi lar to c-jun null mouse embryos and suggests that SEK1 is required for phosphorylation and activation of c-jun during the organo-genesis of the liver.