Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis
-
Cell Differentiation
-
Cell Line
-
Cell Survival
-
Cells, Cultured
-
Cyclin-Dependent Kinase Inhibitor p57
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / pharmacology
-
HeLa Cells
-
Humans
-
JNK Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 1*
-
Mice
-
Mice, Knockout
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinases / metabolism
-
Nuclear Proteins / metabolism
-
Nuclear Proteins / physiology*
-
Plasmids / metabolism
-
Precipitin Tests
-
Protein Binding
-
Protein Serine-Threonine Kinases / metabolism
-
Signal Transduction*
-
Transfection
-
Ultraviolet Rays
Substances
-
CDKN1C protein, human
-
Cdkn1c protein, mouse
-
Cyclin-Dependent Kinase Inhibitor p57
-
Enzyme Inhibitors
-
Nuclear Proteins
-
Protein Serine-Threonine Kinases
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 1
-
MAP3K1 protein, human
-
Map3k1 protein, mouse