p57^KIP2 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.