CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control

J Cell Biol. 2005 Feb 14;168(4):561-6. doi: 10.1083/jcb.200411060. Epub 2005 Feb 7.

Abstract

Nuclear factor kappaB (NF-kappaB) mediates homeostatic growth inhibition in the epidermis, and a loss of NF-kappaB function promotes proliferation and oncogenesis. To identify mechanisms responsible for these effects, we impaired NF-kappaB action in the epidermis by three different genetic approaches, including conditional NF-kappaB blockade. In each case, epidermal hyperplasia was accompanied by an increase in both protein levels and tissue distribution of the G1 cell cycle kinase, CDK4. CDK4 up-regulation required intact TNFR1 and c-Jun NH2-terminal kinase (JNK) function. Cdk4 gene deletion concomitant with conditional NF-kappaB blockade demonstrated that CDK4 is required for growth deregulation. Therefore, epidermal homeostasis depends on antagonist regulation of CDK4 expression by NF-kappaB and TNFR1/JNK.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / metabolism*
  • Epidermis / metabolism*
  • Epidermis / pathology
  • Humans
  • Hyperplasia
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • MAP Kinase Kinase 4
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*

Substances

  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Protein-Serine-Threonine Kinases
  • CDK4 protein, human
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • JNK Mitogen-Activated Protein Kinases
  • NF-kappa B kinase
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases