NFATc2-mediated repression of cyclin-dependent kinase 4 expression

Mol Cell. 2002 Nov;10(5):1071-81. doi: 10.1016/s1097-2765(02)00701-3.

Abstract

The calcineurin-regulated transcription factor, nuclear factor of activated T cells (NFAT), controls many aspects of T cell function. Here, we demonstrate that the calcineurin/NFAT pathway negatively regulates the expression of cyclin-dependent kinase 4 (CDK4). A canonical NFAT binding site was identified and found to be sensitive to calcium signals, FK506/CsA, and histone deacetylase activity and to not require AP-1. Ectopic expression of NFATc2 inhibited the basal activity of the human CDK4 promoter. Additionally, both calcineurin Aalpha(-/-) and NFATc2(-/-) mice had elevated protein levels of CDK4, confirming a negative regulatory role for the calcineurin/NFAT pathway. This pathway may thus regulate the expression of CDK4 at the transcriptional level and control how cells re-enter a resting, nonproliferative state.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Division
  • Chromatin / metabolism
  • Cloning, Molecular
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / biosynthesis*
  • Cyclosporine / pharmacology
  • DNA-Binding Proteins / metabolism*
  • Exons
  • Gene Expression Regulation*
  • Genes, Reporter
  • Histone Deacetylases / metabolism
  • Humans
  • Jurkat Cells
  • Luciferases / metabolism
  • Lymphocytes / metabolism
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Molecular Sequence Data
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Phosphorylation
  • Precipitin Tests
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tacrolimus / pharmacology
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection

Substances

  • Chromatin
  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • NFATC2 protein, human
  • Nfatc2 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Cyclosporine
  • Luciferases
  • CDK4 protein, human
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Histone Deacetylases
  • Tacrolimus