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.
Mesh Terms:
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
J. Biol. Chem.
Date: Nov. 28, 2003
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