14-3-3 proteins block apoptosis and differentially regulate MAPK cascades

14-3-3 family members are dimeric phosphoserine-binding proteins that parti cipate in signal transduction and checkpoint control pathways. In this work , dominant-negative mutant forms of 14-3-3 were used to disrupt 14-3-3 func tion in cultured cells and in transgenic animals. Transfection of cultured fibroblasts with the R56A and R60A double mutant form of 14-3-3 zeta (DN-14 -3-3 zeta) inhibited serum-stimulated ERK MAPK activation, but increased th e basal activation of JNK1 and p38 MAPK. Fibroblasts transfected with DN-14 -3-3 zeta exhibited markedly increased apoptosis in response to UVC irradia tion that was blocked by pretreatment with a p38 MAPK inhibitor, SB202190. Targeted expression of DN-14-3-3 eta to murine postnatal cardiac tissue inc reased the basal activation of JNK1 and p38 MAPK, and affected the ability of mice to compensate for pressure overload, which resulted in increased mo rtality, dilated cardiomyopathy and massive cardiomyocyte apoptosis. These results demonstrate that a primary function of mammalian 14-3-3 proteins is to inhibit apoptosis.