P57KIP2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase/stress-activated protein kinase

p57(KIP2), a member of the Cip/Kip family of enzymes that inhibit several cyclin-dependent kinases, plays a role in many biological events including cell proliferation, differentiation, apoptosis, tumorigenesis and developmental changes. The human p57(KIP2) gene is located in chromosome 11p15.5, a region implicated in sporadic cancers and Beckwith-Wiedemann syndrome. We here report that p57(KIP2) physically interacts with and inhibits c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK). The carboxyl-terminal QT domain of p57(KIP2) is crucial for the inhibition of JNK/ SAPK. Overexpressed p57(KIP2) also suppressed UV- and MEKK1-induced apoptotic cell death. p57(KIP2) expression during C2C12 myoblast differentiation resulted in repression of the JNK activity stimulated by UV light. Furthermore, UV- stimulated JNK1 activity was higher in mouse embryonic fibroblasts derived from p57(-/-) mice than in the cells from wild-type mice. Taken together, these findings suggest that p57(KIP2) modulates stress-activated signaling by functioning as an endogenous inhibitor of JNK/ SAPK.