Abstract
We used primary peripheral blood T cells, a population that exists in G0 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 G0/G1 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 G0/G1 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.
Footnotes
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↵1 Present address: Department of Medicine, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA.
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↵2 Present address: Aegis Creative Communications, Littleton, CO.
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↵3 Present address: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY.
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This study was supported in part by a grant from the Monfort Family Foundation to the University of Colorado Cancer Center and by Grants R55 CA86432 from the National Institutes of Health, RSG-02-173-01-LIB from the American Cancer Society, 0791 from the Smokeless Tobacco Research Council, and by a grant from the Philip Morris External Research Program (to J.F.M.). A.A.F.-A. was supported by a fellowship from the University of Colorado Cancer Center and by Grant NRSA F32 AI50392 from the National Institutes of Health. S.B. was supported by Fellowship 01-047 from the Association for International Cancer Research. H.M. was supported in part by an educational grant (R25 CA49981) from the National Cancer Institute. The University of Colorado Cancer Center Flow Cytometry Core is supported by Grant P30 CA46934 from the National Cancer Institute.
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doi:10.1124/jpet.104.070060.
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ABBREVIATIONS: PBT, peripheral blood T cell; nAChR, nicotinic acetylcholine receptor; Cai2+, intracellular ionized calcium; NFAT, nuclear factor of activated T cells; IL-2, interleukin-2; AP-1, activator protein-1; CDK, cyclin-dependent kinase; PBS, phosphate-buffered saline; FBS, fetal bovine serum; PHA, phytohemagglutinin; HEX, hexamethonium; DHβe, dihydro-β-erythroidin; α-BTX, α-bungarotoxin; dTC, d-tubocurarine; PMA, phorbol myristate acetate; CsA, cyclosporin A; BrdU, bromodeoxyuridine; PCR, polymerase chain reaction; GFP, green fluorescent protein.
- Received April 15, 2004.
- Accepted July 1, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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