Nicotine Activates Nuclear Factor of Activated T Cells c2 (NFATc2) and Prevents Cell Cycle Entry in T Cells

Authors:
Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, Linthicum DS, Burakoff SJ, Coons T, Bellgrau D and Modiano JF
In:
Source: J Pharmacol Exp Ther
Publication Date: (2004)
Issue: 311(2): 758-769
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Jurkat
Species: human
Tissue Origin: blood
Jurkat-modified
Species: human
Tissue Origin:
Platform:
Nucleofectorâ„¢ I/II/2b
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.