title: Nicotine activates nuclear factor of activated T cells c2 (NFATc2) and prevents cell cycle entry in T cells.
abstract: We used primary peripheral blood T cells, a population that exists in G(0) and can be stimulated to enter the cell cycle synchronously, to define more precisely the effects of nicotine on pathways that control cell cycle entry and progression. Our data show that nicotine decreased the ability of T cells to transit through the G(0)/G(1) boundary (acquire competence) and respond to progression signals. These effects were due to nuclear factor of activated T cells c2 (NFATc2)-dependent repression of cyclin-dependent kinase 4 (CDK4) expression. Growth arrest at the G(0)/G(1) boundary was further enforced by inhibition of cyclin D2 expression and by increased expression and stabilization of p27Kip1. Intriguingly, T cells from habitual users of tobacco products and from NFATc2-deficient mice constitutively expressed CDK4 and were resistant to the antiproliferative effects of nicotine. These results indicate that nicotine impairs T cell cycle entry through NFATc2-dependent mechanisms and suggest that, in the face of chronic nicotine exposure, selection may favor cells that can evade these effects. We postulate that cross talk between nicotinic acetylcholine receptors and growth factor receptor-activated pathways offers a novel mechanism by which nicotine may directly impinge on cell cycle progression. This offers insight into possible reasons that underlie the unique effects of nicotine on distinct cell types and identifies new targets that may be useful control tobacco-related diseases.
authors.affiliation: Integrated Department of Immunology, University of Colorado Health Sciences Center, AMC Cancer Center, 2-Diamond Building, 1600 Pierce Street, Denver, CO 80214, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Frazer-Abel
authors.forename: Shairaz
authors.initials: S
authors.lastname: Baksh
authors.forename: Susan P
authors.initials: SP
authors.lastname: Fosmire
authors.forename: Derall
authors.initials: D
authors.lastname: Willis
authors.forename: Angela M
authors.initials: AM
authors.lastname: Pierce
authors.forename: Heather
authors.initials: H
authors.lastname: Meylemans
authors.forename: Darwin S
authors.initials: DS
authors.lastname: Linthicum
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burakoff
authors.forename: Teresa
authors.initials: T
authors.lastname: Coons
authors.forename: Donald
authors.initials: D
authors.lastname: Bellgrau
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors; D009538:Nicotine / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014026:Nicotiana / Q000737:chemistry; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D009538:Nicotine; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D002118:Calcium