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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 1, 2004; DOI: 10.1124/jpet.104.070060

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Received for publication April 19, 2004.
Revised June 20, 2004.
Accepted for publication July 1, 2004.

Nicotine Activates NFATc2 and Prevents Cell Cycle Entry in T Cells

Ashley A Frazer-Abel 1, Shairaz Baksh 2, Susan P Fosmire 1, Derall Willis 3, Angela M Pierce 1, Heather Meylemans 1, Darwin S Linthicum 4, Steven J Burakoff 2, Teresa Coons 3, Donald Bellgrau 1, Jaime F. Modiano 5*

1 University of Colorado Health Sciences Center, Denver, CO 2 Harvard Medical School, Boston, MA 3 Saccomanno Research Institute, Grand Junction, CO 4 Landcare Research, Lincoln, New Zealand 5 University of Colorado Health Sciences Center

* Address correspondence to: E-mail: modianoj{at}amc.org

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 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 anti-proliferative 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 crosstalk 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.


Key words: Cell Cycle, Human, Mouse, Nicotine, T Lymphocytes, Transcription Factors


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