p57KIP2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase/stress-activated protein Kinase.
p57KIP2, 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 p57KIP2 gene is located in chromosome 11p15.5, a region implicated in sporadic cancers and Beckwith-Wiedemann syndrome. We here report that p57KIP2 physically interacts with and inhibits c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK). The carboxyl-terminal QT domain of p57KIP2 is crucial for the inhibition of JNK/SAPK. Overexpressed p57KIP2 also suppressed UV- and MEKK1-induced apoptotic cell death. p57KIP2 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 p57KIP2 modulates stress-activated signaling by functioning as an endogenous inhibitor of JNK/SAPK.
Pubmed ID: 12963725 RIS Download
Animals | Apoptosis | Cell Differentiation | Cell Line | Cell Survival | Cells, Cultured | Cyclin-Dependent Kinase Inhibitor p57 | Dose-Response Relationship, Drug | Enzyme Inhibitors | HeLa Cells | Humans | JNK Mitogen-Activated Protein Kinases | MAP Kinase Kinase Kinase 1 | Mice | Mice, Knockout | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinases | Nuclear Proteins | Plasmids | Precipitin Tests | Protein Binding | Protein-Serine-Threonine Kinases | Signal Transduction | Transfection | Ultraviolet Rays