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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

Authors

  • Chang TS
  • Kim MJ
  • Ryoo K
  • Park J
  • Eom SJ
  • Shim J
  • Nakayama KI
  • Nakayama K
  • Tomita M
  • Takahashi K
  • Lee MJ
  • Choi EJ

Journal

The Journal of biological chemistry

Publication Data

November 28, 2003

Associated Grants

None

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