Nicotine activates nuclear factor of activated T cells c2 (NFATc2) and prevents cell cycle entry in T cells

Ashley A. Frazer-Abel, Shairaz Baksh, Susan P. Fosmire, Derail Willis, Angela M. Pierce, Heather Meylemans, Darwin S. Linthicum, Steven J. Burakoff, Teresa Coons, Donald Bellgrau, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 G 0/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.

Original languageEnglish (US)
Pages (from-to)758-769
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number2
DOIs
StatePublished - Nov 2004

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