Journal
FASEB JOURNAL
Volume 22, Issue 5, Pages 1356-1368Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.07-9965.com
Keywords
nicotinic acetylcholine receptors; Akt; PKC; p38; JAK-2; GATA-2
Categories
Funding
- NCI NIH HHS [CA117327] Funding Source: Medline
- NIDCR NIH HHS [DE14173] Funding Source: Medline
- NIEHS NIH HHS [ES014384] Funding Source: Medline
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Tobacco products and nicotine alter the cell cycle and lead to squamatization of oral keratinocytes (KCs) and squamous cell carcinoma. Activation of nicotinic acetylcholine receptors (nAChRs) elicits Ca(2+) influx that varies in magnitude between different nAChR subtypes. Normal differentiation of KCs is associated with sequential expression of the nAChR subtypes with increasing Ca(2+) permeability, such as alpha 5-containing alpha 3 nAChR and alpha 7 nAChR. Exposure to environmental tobacco smoke (ETS) or an equivalent concentration of nicotine accelerated by severalfold the alpha 5 and alpha 7 expression in KCs, which could be abolished by mecamylamine and et-bungarotoxin with different efficacies, suggesting the following sequence of autoregulation of the expression of nAChR subtypes: alpha 3(beta 2/beta 4) > alpha 3(beta 2/beta 4)alpha 5 > alpha 7 > alpha 7. This conjecture was corroborated by results of quantitative assays of subunit mRNA and protein levels, using nAChR-specific pharmacologic antagonists and small interfering RNAs. The genomic effects of ETS and nicotine involved the transcription factor GATA-2 that showed a multifold increase in quantity and activity in exposed KCs. Using protein kinase inhibitors and dominant negative and constitutively active constructs, we characterized the principal signaling cascades mediating a switch in the nAChR subtype. Cumulative results indicated that the alpha 3(beta 2/beta 4) to alpha 3(beta 2/beta 4)alpha 5 nAChR transition predominantly involved protein kinase C, alpha 3(beta 2/beta 4)alpha 5 to alpha 7 nAChR transition-Ca(2+)/calmodulin-dependent protein kinase II and p38 MAPK, and alpha 7 self-up-regulation-the p38 MAPK/Akt pathway, and JAK-2. These results provide a mechanistic insight into the genomic effects of ETS and nicotine on KCs and characterize signaling pathways mediating autoregulation of stepwise overexpression of nAChR subtypes with increasing Ca(2+) permeability in exposed cells. These observations have salient clinical implications, because a switch in the nAChR subunit composition can bring about a corresponding switch in receptor function, leading to profound pathobiologic effects observed in KCs exposed to tobacco products.
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