NFATc2-mediated repression of cyclin-dependent kinase 4 expression.
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.
Baksh
Shairaz
S
Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
Widlund
Hans R
HR
Frazer-Abel
Ashley A
AA
Du
Jinyan
J
Fosmire
Susan
S
Fisher
David E
DE
DeCaprio
James A
JA
Modiano
Jaime F
JF
Burakoff
Steven J
SJ
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
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