JNK and cellular stress–induced apoptosis.

JNK signaling has been implicated in proliferation, differentiation, and cellular stress–induced apoptosis. The effects of JNK on cellular apoptosis depend strongly on the cell type and the context of other regulatory influences. JNK signaling can be turned off by dual-specificity MAPK phosphatases. JNK activation results in phosphorylation of AP-1 transcription factor family members such as c-Jun and ATF-2, which then bind to AP-1 binding sites in the promoters of multiple target genes. JNK may contribute to death receptor transcription-dependent apoptotic signaling via c-Jun/AP-1 (leading to promoter induction of CD95-L, TNF-α, and p53) to transcription-independent apoptotic signaling by phosphorylation-dependent posttranslational proapoptotic processes (leading to cytochrome c release, stabilization of p53 protein, inactivation of Bcl-2, Bcl-X_L, and activation of c-myc). These mechanisms may function separately or cooperate in induction of apoptosis. JNK signaling in combination with other factors, eg, the suppression of proliferation pathways, may mediate cellular stress–induced apoptosis.