title: NFATc2-mediated repression of cyclin-dependent kinase 4 expression.
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.
authors.affiliation: Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shairaz
authors.initials: S
authors.lastname: Baksh
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Frazer-Abel
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Susan
authors.initials: S
authors.lastname: Fosmire
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burakoff
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis*; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005091:Exons; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D008156:Luciferases; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases; D016559:Tacrolimus