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