Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

From smoking to lung cancer: the CHRNA5/A3/B4 connection

Abstract

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster encoding the α3, α5 and β4 nAChR subunits received heightened interest after a succession of linkage analyses and association studies identified multiple single-nucleotide polymorphisms in these genes that are associated with an increased risk for nicotine dependence and lung cancer. It is not clear whether the risk for lung cancer is direct or an effect of nicotine dependence, as evidence for both scenarios exist. In this study, we summarize the body of work implicating nAChRs in the pathogenesis of lung cancer, with special focus on the clustered nAChR subunits and their emerging role in this disease state.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • ACS (2009). Cancer Facts And Figures 2009. American Cancer Society: Atlanta, Georgia, USA, pp 1–68.

  • Albuquerque EX, Pereira EF, Alkondon M, Rogers SW . (2009). Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89: 73–120.

    Article  CAS  PubMed  Google Scholar 

  • Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T et al. (2008). Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40: 616–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arneric SP, Holladay M, Williams M . (2007). Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem Pharmacol 74: 1092–1101.

    Article  CAS  PubMed  Google Scholar 

  • Arredondo J, Chernyavsky AI, Grando SA . (2006a). The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells. J Cancer Res Clin Oncol 132: 653–663.

    Article  CAS  PubMed  Google Scholar 

  • Arredondo J, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA . (2006b). Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J 20: 2093–2101.

    Article  CAS  PubMed  Google Scholar 

  • Arredondo J, Nguyen VT, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA . (2001). A receptor-mediated mechanism of nicotine toxicity in oral keratinocytes. Lab Invest 81: 1653–1668.

    Article  CAS  PubMed  Google Scholar 

  • Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H et al. (1993). Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci USA 90: 5648–5652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Battaglioli E, Gotti C, Terzano S, Flora A, Clementi F, Fornasari D . (1998). Expression and transcriptional regulation of the human alpha3 neuronal nicotinic receptor subunit in T lymphocyte cell lines. J Neurochem 71: 1261–1270.

    Article  CAS  PubMed  Google Scholar 

  • Benfante R, Flora A, Di Lascio S, Cargnin F, Longhi R, Colombo S et al. (2007). Transcription factor PHOX2A regulates the human α3 nicotinic receptor subunit gene promoter. J Biol Chem 282: 13290–13302.

    Article  CAS  PubMed  Google Scholar 

  • Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H et al. (2008). Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13: 368–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X et al. (2008). Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165: 1163–1171.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bigger CB, Melnikova IN, Gardner PD . (1997). Sp1 and Sp3 regulate expression of the neuronal nicotinic acetylcholine receptor β4 subunit gene. J Biol Chem 272: 25976–25982.

    Article  CAS  PubMed  Google Scholar 

  • Blanchet MR, Israël-Assayag E, Cormier Y . (2004). Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 169: 903–909.

    Article  PubMed  Google Scholar 

  • Boulter J, O'Shea-Greenfield A, Duvoisin RM, Connolly JG, Wada E, Jensen A et al. (1990). Alpha 3, alpha 5, and beta 4: three members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem 265: 4472–4482.

    CAS  PubMed  Google Scholar 

  • Boyd RT . (1997). The molecular biology of neuronal nicotinic acetylcholine receptors. Crit Rev Toxicol 27: 299–318.

    Article  CAS  PubMed  Google Scholar 

  • Bruschweiler-Li L, Fuentes Medel YF, Scofield MD, Trang EBT, Binke SA, Gardner PD . (2010). Temporally- and spatially-regulated transcriptional activity of the nicotinic acetylcholine receptor β4 subunit gene promoter region. Neurosci 166: 864–877.

    Article  CAS  Google Scholar 

  • Calabresi P, Lacey MG, North RA . (1989). Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording. Br J Pharmacol 98: 135–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campos-Caro A, Carrasco-Serrano C, Valor LM, Ballesta JJ, Criado M . (2001). Activity of the nicotinic acetylcholine receptor alpha5 and alpha7 subunit promoters in muscle cells. DNA Cell Biol 20: 657–666.

    Article  CAS  PubMed  Google Scholar 

  • Campos-Caro A, Carrasco-Serrano C, Valor LM, Viniegra S, Ballesta JJ, Criado M . (1999). Multiple functional Sp1 domains in the minimal promoter region of the neuronal nicotinic receptor alpha5 subunit gene. J Biol Chem 274: 4693–4701.

    Article  CAS  PubMed  Google Scholar 

  • Caporaso N, Gu F, Chatterjee N, Sheng-Chih J, Yu K, Yeager M et al. (2009). Genome-wide and candidate gene association study of cigarette smoking behaviors. PLoS One 4: e4653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • CDC (2009). Cigarette Smoking among Adults and Trends in Smoking Cessation—United States, 2008. Centers for Disease Control and Prevention 58: 1227–1232.

    Google Scholar 

  • Conklin BS, Zhao W, Zhong DS, Chen C . (2002). Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol 160: 413–418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conti-Fine BM, Navaneetham D, Lei S, Maus AD . (2000). Neuronal nicotinic receptors in non-neuronal cells: new mediators of tobacco toxicity? Eur J Pharmacol 393: 279–294.

    Article  CAS  PubMed  Google Scholar 

  • Cooke JP, Ghebremariam YT . (2008). Endothelial nicotinic acetylcholine receptors and angiogenesis. Trends Cardiovasc Med 18: 247–253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corrigall WA, Coen KM . (1991). Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology (Berl) 104: 171–176.

    Article  CAS  Google Scholar 

  • Corrigall WA, Franklin KB, Coen KM, Clarke PB . (1992). The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107: 285–289.

    Article  CAS  Google Scholar 

  • Corrigall WA, Herling S, Coen KM . (1989). Evidence for a behavioral deficit during withdrawal from chronic nicotine treatment. Pharmacol Biochem Behav 33: 559–562.

    Article  CAS  PubMed  Google Scholar 

  • Corringer PJ, Le Novere N, Changeux J-P . (2000). Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol 40: 431–458.

    Article  CAS  PubMed  Google Scholar 

  • Corriveau RA, Berg DK . (1993). Coexpression of multiple acetylcholine receptor genes in neurons: quantification of transcripts during development. J Neurosci 13: 2662–2671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couturier S, Bertrand D, Matter JM, Hernandez MC, Bertrand S, Millar N et al. (1990). A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX. Neuron 5: 847–856.

    Article  CAS  PubMed  Google Scholar 

  • Dani JA, Bertrand D . (2007). Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47: 699–729.

    Article  CAS  PubMed  Google Scholar 

  • Dani JA, De Biasi M . (2001). Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70: 439–446.

    Article  CAS  PubMed  Google Scholar 

  • Dasgupta P, Chellappan SP . (2006). Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story. Cell Cycle 5: 2324–2328.

    Article  CAS  PubMed  Google Scholar 

  • Davis R, Rizwani W, Banerjee S, Kovacs M, Haura E, Coppola D et al. (2009). Nicotine promotes tumor growth and metastasis in mouse models of lung cancer. PLoS One 4: e7524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Biasi M, Salas R . (2008). Influence of neuronal nicotinic receptors over nicotine addiction and withdrawal. Exp Biol Med 233: 917–929.

    Article  CAS  Google Scholar 

  • Di Chiara G . (2000). Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393: 295–314.

    Article  CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A . (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du Q, Melnikova IN, Gardner PD . (1998). Differential effects of heterogeneous nuclear ribonucleoprotein K on Sp1- and Sp3-mediated transcriptional activation of a neuronal nicotinic acetylcholine receptor promoter. J Biol Chem 273: 19877–19883.

    Article  CAS  PubMed  Google Scholar 

  • Du Q, Tomkinson AE, Gardner PD . (1997). Transcriptional regulation of neuronal nicotinic acetylcholine receptor genes. A possible role for the DNA-binding protein Puralpha. J Biol Chem 272: 14990–14995.

    Article  CAS  PubMed  Google Scholar 

  • Egleton RD, Brown KC, Dasgupta P . (2008). Nicotinic acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. Trends Pharmacol Sci 29: 151–158.

    Article  CAS  PubMed  Google Scholar 

  • Elgoyhen AB, Johnson DS, Boulter J, Vetter DE, Heinemann S . (1994). Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79: 705–715.

    Article  CAS  PubMed  Google Scholar 

  • Elgoyhen AB, Vetter DE, Katz E, Rothlin CV, Heinemann SF, Boulter J . (2001). alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc Natl Acad Sci USA 98: 3501–3506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Falvella FS, Galvan A, Frullanti E, Spinola M, Calabro E, Carbone A et al. (2009). Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk. Clin Cancer Res 15: 1837–1842.

    Article  CAS  PubMed  Google Scholar 

  • Flora A, Schulz R, Benfante R, Battaglioli E, Terzano S, Clementi F et al. (2000a). Transcriptional regulation of the human alpha5 nicotinic receptor subunit gene in neuronal and non-neuronal tissues. Eur J Pharmacol 393: 85–95.

    Article  CAS  PubMed  Google Scholar 

  • Flora A, Schulz R, Benfante R, Battaglioli E, Terzano S, Clementi F et al. (2000b). Neuronal and extraneuronal expression and regulation of the human alpha5 nicotinic receptor subunit gene. J Neurochem 75: 18–27.

    Article  CAS  PubMed  Google Scholar 

  • Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN et al. (2009). A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Hum Mol Genet 18: 2922–2927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fucile S . (2004). Ca2+ permeability of nicotinic acetylcholine receptors. Cell Calcium 35: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Gahring LC, Persiyanov K, Dunn D, Weiss R, Meyer EL, Rogers SW . (2004). Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus. J Comp Neurol 468: 334–346.

    Article  CAS  PubMed  Google Scholar 

  • Gahring LC, Rogers SW . (2006). Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells. AAPS J 7: E885–E894.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gerzanich V, Kuryatov A, Anand R, Lindstrom J . (1997). Orphan’ alpha6 nicotinic AChR subunit can form a functional heteromeric acetylcholine receptor. Mol Pharmacol 51: 320–327.

    Article  CAS  PubMed  Google Scholar 

  • Gerzanich V, Wang F, Kuryatov A, Lindstrom J . (1998). alpha 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors. J Pharmacol Exp Ther 286: 311–320.

    CAS  PubMed  Google Scholar 

  • Gotti C, Zoli M, Clementi F . (2006). Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 27: 482–491.

    Article  CAS  PubMed  Google Scholar 

  • Grando SA . (2008). Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors. J Pharmacol Sci 106: 174–179.

    Article  CAS  PubMed  Google Scholar 

  • Greenbaum L, Lerer B . (2009). Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions. Mol Psychiatry 14: 912–945.

    Article  CAS  PubMed  Google Scholar 

  • Grivennikov SI, Greten FR, Karin M . (2010). Immunity, inflammation, and cancer. Cell 140: 883–899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hecht SS, Hoffmann D . (1988). Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9: 875–884.

    Article  CAS  PubMed  Google Scholar 

  • Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS et al. (2001). Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 7: 833–839.

    Article  CAS  PubMed  Google Scholar 

  • HHS (2004). 2004 Surgeon General's Report—The Health Consequences of Smoking. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General.

  • Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D et al. (2008). A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452: 633–637.

    Article  CAS  PubMed  Google Scholar 

  • Improgo MRD, Schlichting NA, Cortes RY, Zhao-Shea R, Tapper AR, Gardner PD . (2010). ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Mol Cancer Res 8: 194–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackman DM, Johnson B . (2005). Small-cell lung cancer. Lancet 366: 1385–1396.

    Article  CAS  PubMed  Google Scholar 

  • Jackson KJ, Martin BR, Changeux JP, Damaj MI . (2008). Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther 325: 302–312.

    Article  CAS  PubMed  Google Scholar 

  • Jin Z, Gao F, Flagg T, Deng X . (2004). Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. J Biol Chem 279: 23837–23844.

    Article  CAS  PubMed  Google Scholar 

  • Jull BA, Plummer III HK, Schuller HM . (2001). Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway, resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells. J Cancer Res Clin Oncol 127: 707–717.

    CAS  PubMed  Google Scholar 

  • Karlin A . (2002). Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3: 102–114.

    Article  CAS  PubMed  Google Scholar 

  • Kawashima K, Fujii T . (2003). The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 74: 675–696.

    Article  CAS  PubMed  Google Scholar 

  • Kenny PJ, Markou A . (2001). Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 70: 531–549.

    Article  CAS  PubMed  Google Scholar 

  • Klink R, de Kerchove d'Exaerde A, Zoli M, Changeux JP . (2001). Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21: 1452–1463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lam DC, Girard L, Ramirez R, Chau W, Suen W, Sheriden S et al. (2007). Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res 67: 4638–4647.

    Article  CAS  PubMed  Google Scholar 

  • Le Novere N, Changeux JP . (1995). Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J Mol Evol 40: 155–172.

    Article  CAS  PubMed  Google Scholar 

  • Leonard S, Bertrand D . (2001). Neuronal nicotinic receptors: from structure to function. Nicotine Tob Res 3: 203–223.

    Article  CAS  PubMed  Google Scholar 

  • Levey MS, Brumwell CL, Dryer SE, Jacob MH . (1995). Innervation and target tissue interactions differentially regulate acetylcholine receptor subunit mRNA levels in developing neurons in situ. Neuron 14: 153–162.

    Article  CAS  PubMed  Google Scholar 

  • Levey MS, Jacob MH . (1996). Changes in the regulatory effects of cell-cell interactions on neuronal AChR subunit transcript levels after synapse formation. J Neurosci 16: 6878–6885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linnoila RI, Zhao B, DeMayo JL, Nelkin BD, Baylin SB, DeMayo FJ et al. (2000). Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res 60: 4005–4009.

    CAS  PubMed  Google Scholar 

  • Liu P, Vikis HG, Wang D, Lu Y, Wang Y, Schwartz AG et al. (2008). Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst 100: 1326–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Huang Y, Xue F, Simard A, DeChon J, Li G et al. (2009). A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. J Neurosci 29: 918–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Melnikova IN, Hu M, Gardner PD . (1999). Cell type-specific activation of neuronal nicotinic acetylcholine receptor subunit genes by Sox10. J Neurosci 19: 9747–9755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lloyd GK, Williams M . (2000). Neuronal nicotinic acetylcholine receptors as novel drug targets. J Pharmacol Exp Ther 292: 461–467.

    CAS  PubMed  Google Scholar 

  • Lustig LR, Peng H, Hiel H, Yamamoto T, Fuchs PA . (2001). Molecular cloning and mapping of the human nicotinic acetylcholine receptor alpha10 (CHRNA10). Genomics 73: 272–283.

    Article  CAS  PubMed  Google Scholar 

  • Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM . (1998). Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharmacol Exp Ther 287: 435–439.

    CAS  PubMed  Google Scholar 

  • Mai H, May WS, Gao F, Jin Z, Deng X . (2003). A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 278: 1886–1891.

    Article  CAS  PubMed  Google Scholar 

  • Maneckjee R, Minna JD . (1990). Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proc Natl Acad Sci USA 87: 3294–3298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maneckjee R, Minna JD . (1994). Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ 5: 1033–1040.

    CAS  PubMed  Google Scholar 

  • Marubio LM, Gardier AM, Durier S, David D, Klink R, Arroyo-Jimenez MM et al. (2003). Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci 17: 1329–1337.

    Article  CAS  PubMed  Google Scholar 

  • Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP et al. (2005). Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436: 103–107.

    Article  CAS  PubMed  Google Scholar 

  • Maus AD, Pereira EF, Karachunski PI, Horton RM, Navaneetham D, Macklin K et al. (1998). Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol 54: 779–788.

    Article  CAS  PubMed  Google Scholar 

  • McGehee DS, Role LW . (1995). Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol 57: 521–546.

    Article  CAS  PubMed  Google Scholar 

  • McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ . (2009). Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 66: 735–741.

    PubMed  PubMed Central  Google Scholar 

  • Melnikova IN, Gardner PD . (2001). The signal transduction pathway underlying ion channel gene regulation by SP1-C-Jun interactions. J Biol Chem 276: 19040–19045.

    Article  CAS  PubMed  Google Scholar 

  • Melnikova IN, Lin HR, Blanchette AR, Gardner PD . (2000). Synergistic transcriptional activation by Sox10 and Sp1 family members. Neuropharm 39: 2615–2623.

    Article  CAS  Google Scholar 

  • Milton NG, Bessis A, Changeux JP, Latchman DS . (1996). Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors. Biochem J 317 (Pt 2): 419–423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen VT, Hall LL, Gallacher G, Ndoye A, Jolkovsky DL, Webber RJ et al. (2000). Choline acetyltransferase, acetylcholinesterase, and nicotinic acetylcholine receptors of human gingival and esophageal epithelia. J Dent Res 79: 939–949.

    Article  CAS  PubMed  Google Scholar 

  • Nisell M, Nomikos GG, Svensson TH . (1994). Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16: 36–44.

    Article  CAS  PubMed  Google Scholar 

  • Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D . (2005). Increased severity of experimental colitis in alpha 5 nicotinic acetylcholine receptor subunit-deficient mice. NeuroReport 16: 1123–1127.

    Article  CAS  PubMed  Google Scholar 

  • Paliwal A, Vaissière T, Krais A, Cuenin C, Cros MP, Zaridze D et al. (2010). Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer. Cancer Res 70: 2779–2788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patrick J, Sequela P, Vernino S, Amador M, Luetje C, Dani JA . (1993). Functional diversity of neuronal nicotinic acetylcholine receptors. Prog Brain Res 98: 113–120.

    Article  CAS  PubMed  Google Scholar 

  • Perry DC, Xiao Y, Nguyen HN, Musachio JL, Davila-Garcia MI, Kellar KJ . (2002). Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem 82: 468–481.

    Article  CAS  PubMed  Google Scholar 

  • Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM et al. (1998). Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391: 173–177.

    Article  CAS  PubMed  Google Scholar 

  • Pidoplichko VI, DeBiasi M, Williams JT, Dani JA . (1997). Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390: 401–404.

    Article  CAS  PubMed  Google Scholar 

  • Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC et al. (2009). A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 5: e1000421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM et al. (2008). Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28: 12318–12327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pontieri FE, Tanda G, Orzi F, Di Chiara G . (1996). Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382: 255–257.

    Article  CAS  PubMed  Google Scholar 

  • Portugal GS, Gould TJ . (2008). Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research. Behav Brain Res 193: 1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Portugal GS, Kenney JW, Gould TJ . (2008). Beta2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning. Neurobiol Learn Mem 89: 106–113.

    Article  CAS  PubMed  Google Scholar 

  • Pugh BF, Tjian R . (1991). Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Dev 5: 1935–1945.

    Article  CAS  PubMed  Google Scholar 

  • Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM . (2009). Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. J Natl Cancer Inst 101: 554–559.

    Article  PubMed  PubMed Central  Google Scholar 

  • Quick MW, Ceballos RM, Kasten M, McIntosh JM, Lester RA . (1999). Alpha3beta4 subunit-containing nicotinic receptors dominate function in rat medial habenula neurons. Neuropharmacology 38: 769–783.

    Article  CAS  PubMed  Google Scholar 

  • Richardson CE, Morgan JM, Jasani B, Green JT, Rhodes J, Williams GT et al. (2001). Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit. Gastroenterology 121: 350–357.

    Article  CAS  PubMed  Google Scholar 

  • Role LW, Berg DK . (1996). Nicotinic receptors in the development and modulation of CNS synapses. Neuron 16: 1077–1085.

    Article  CAS  PubMed  Google Scholar 

  • Romanelli MN, Gratteri P, Guandalini L, Martini E, Bonaccini C, Gualtieri F . (2007). Central nicotinic receptors: structure, function, ligands, and therapeutic potential. ChemMedChem 2: 746–767.

    Article  CAS  PubMed  Google Scholar 

  • Rubin DT, Hanauer SB . (2000). Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 12: 855–862.

    Article  CAS  PubMed  Google Scholar 

  • Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML et al. (2009a). Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 150B: 453–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF et al. (2009b). The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 69: 6848–6856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA et al. (2007). Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16: 36–49.

    Article  CAS  PubMed  Google Scholar 

  • Salas R, Cook KD, Bassetto L, De Biasi M . (2004a). The α3 and β4 nicotinic receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology 47: 401–407.

    Article  CAS  PubMed  Google Scholar 

  • Salas R, Main A, Gangitano D, De Biasi M . (2007). Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit. Neuropharmacology 53: 863–869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salas R, Pieri F, De Biasi M . (2004b). Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24: 10035–10039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salas R, Pieri F, Fung B, Dani JA, De Biasi M . (2003). Altered anxiety-related responses in mutant mice lacking the beta4 subunit of the nicotinic receptor. J Neurosci 23: 6255–6263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salminen O, Murphy KL, McIntosh JM, Drago J, Marks MJ, Collins AC et al. (2004). Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol 65: 1526–1535.

    Article  CAS  PubMed  Google Scholar 

  • Sartelet H, Maouche K, Totobenazara JL, Petit J, Burlet H, Monteau M et al. (2008). Expression of nicotinic receptors in normal and tumoral pulmonary neuroendocrine cells (PNEC). Pathol Res Pract 204: 891–898.

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Hikosaka Y, Okuda K, Kawano O, Yukiue H, Yano M et al. (2010). CHRNA5 gene D398N polymorphism in Japanese lung adenocarcinoma. J Surg Res 162: 75–78.

    Article  CAS  PubMed  Google Scholar 

  • Scheid MP, Woodgett JR . (2001). PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2: 760–768.

    Article  CAS  PubMed  Google Scholar 

  • Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ et al. (2008). The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 63: 1039–1046.

    Article  CAS  PubMed  Google Scholar 

  • Schoepfer R, Conroy WG, Whiting P, Gore M, Lindstrom J . (1990). Brain alpha-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily. Neuron 5: 35–48.

    Article  CAS  PubMed  Google Scholar 

  • Schuller HM . (1989). Cell type specific, receptor-mediated modulation of growth kinetics in human lung cancer cell lines by nicotine and tobacco-related nitrosamines. Biochem Pharmacol 38: 3439–3442.

    Article  CAS  PubMed  Google Scholar 

  • Schuller HM . (1992). Nitrosamine-induced lung carcinogenesis and Ca2+/calmodulin antagonists. Cancer Res 52: 2723s–22726s.

    CAS  PubMed  Google Scholar 

  • Schuller HM . (2009). Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nat Rev Cancer 9: 195–205.

    Article  CAS  PubMed  Google Scholar 

  • Schuller HM, Orloff M . (1998). Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells. Biochem Pharmacol 55: 1377–1384.

    Article  CAS  PubMed  Google Scholar 

  • Scofield MD, Bruschweiler-Li L, Mou Z, Gardner PD . (2008). Transcription factor assembly on the nicotinic receptor beta4 subunit gene promoter. NeuroReport 19: 687–690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sher E, Codignola A, Passafaro M, Tarroni P, Magnelli V, Carbone E et al. (1998). Nicotinic receptors and calcium channels in small cell lung carcinoma. Functional role, modulation, and autoimmunity. Ann NY Acad Sci 841: 606–624.

    Article  CAS  PubMed  Google Scholar 

  • Sherva R, Wilhelmsen K, Pomerleau CS, Chasse SA, Rice JP, Snedecor SM et al. (2008). Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking. Addiction 103: 1544–1552.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shields PG . (2002). Molecular epidemiology of smoking and lung cancer. Oncogene 21: 6870–6876.

    Article  CAS  PubMed  Google Scholar 

  • Shin VY, Wu WK, Ye YN, So WH, Koo MW, Liu ES et al. (2004). Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2. Carcinogenesis 25: 2487–2495.

    Article  CAS  PubMed  Google Scholar 

  • Shivji M, Burger S, Moncada CA, Clarkson ABJ, Merali S . (2005). Effect of nicotine on lung S-adenosylmethionine and development of Pneumocystis pneumonia. J Biol Chem 280: 15219–15228.

    Article  CAS  PubMed  Google Scholar 

  • Song P, Sekhon HS, Jia Y, Keller JA, Blusztajn JK, Mark GP et al. (2003). Acetycholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res 63: 214–221.

    CAS  PubMed  Google Scholar 

  • Spindel ER . (2003). Neuronal nicotinic acetylcholine receptors: not just in brain. Am J Physiol Lung Cell Mol Physiol 285: L1201–L1202.

    Article  CAS  PubMed  Google Scholar 

  • Spitz MR, Amos CI, Dong Q, Lin J, Wu X . (2008). The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst 100: 1552–1556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stevens VL, Bierut LJ, Talbot JT, Wang JC, Sun J, Hinrichs AL et al. (2008). Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev 17: 3517–3525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stolerman IP, Jarvis MJ . (1995). The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117: 2–10; discussion 14–20.

    Article  CAS  Google Scholar 

  • Sun X, Ritzenthaler JD, Zhong X, Zheng Y, Roman J, Han S . (2009). Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha. Cancer Res 69: 6445–6453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M . (2010). Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 17: 89–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taly A, Corringer PJ, Guedin D, Lestage P, Changeux JP . (2009). Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 8: 733–750.

    Article  CAS  PubMed  Google Scholar 

  • Tapper AR, McKinney SL, Marks MJ, Lester HA . (2007). Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Physiol Genomics 31: 422–428.

    Article  CAS  PubMed  Google Scholar 

  • Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C et al. (2004). Nicotine activation of alpha4*receptors: sufficient for reward, tolerance, and sensitization. Science 306: 1029–1032.

    Article  CAS  PubMed  Google Scholar 

  • Terzano S, Flora A, Clementi F, Fornasari D . (2000). The minimal promoter of the human alpha 3 nicotinic receptor subunit gene. Molecular and functional characterization. J Biol Chem 275: 41495–41503.

    Article  CAS  PubMed  Google Scholar 

  • Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP et al. (2008). A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452: 638–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner JR, Kellar KJ . (2005). Nicotinic cholinergic receptors in the rat cerebellum: multiple heteromeric subtypes. J Neurosci 25: 9258–9265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Unwin N . (2005). Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346: 967–989.

    Article  CAS  PubMed  Google Scholar 

  • Valor LM, Campos-Caro A, Carrasco-Serrano C, Ortiz JA, Ballesta JJ, Criado M . (2002). Transcription factors NF-Y and Sp1 are important determinants of the promoter activity of the bovine and human neuronal nicotinic receptor beta 4 subunit genes. J Biol Chem 277: 8866–8876.

    Article  CAS  PubMed  Google Scholar 

  • Vernino S, Adamski J, Kryzer TJ, Fealey RD, Lennon VA . (1998). Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 50: 1806–1813.

    Article  CAS  PubMed  Google Scholar 

  • Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA . (2000). Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 343: 847–855.

    Article  CAS  PubMed  Google Scholar 

  • Wacholder S, Chatterjee N, Caporaso N . (2008). Intermediacy and gene-environment interaction: the example of CHRNA5-A3 region, smoking, nicotine dependence, and lung cancer. J Natl Cancer Inst 100: 1488–1491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang N, Orr-Urtreger A, Chapman J, Rabinowitz R, Nachman R, Korczyn AD . (2002). Autonomic function in mice lacking alpha5 neuronal nicotinic acetylcholine receptor subunit. J Physiol 542: 347–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang N, Orr-Urtreger A, Chapman J, Rabinowitz R, Korczyn AD . (2003). Deficiency of nicotinic acetylcholine receptor beta 4 subunit causes autonomic cardiac and intestinal dysfunction. Mol Pharmacol 63: 574–580.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Pereira EF, Maus AD, Ostlie NS, Navaneetham D, Lei S et al. (2001). Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors. Mol Pharmacol 60: 1201–1209.

    Article  CAS  PubMed  Google Scholar 

  • Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N et al. (2008). A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 4: e1000125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wessler I, Kirkpatrick CJ . (2008). Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154: 1558–1571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM et al. (2003). Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest 111: 81–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO (2009). WHO Report on the Global Tobacco Epidemic, 2009: Implementing Smoke-Free Environments. World Health Organization.

  • Xin M, Deng X . (2005). Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem 280: 10781–10789.

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Gelber S, Orr-Urtreger A, Armstrong D, Lewis RA, Ou C-N et al. (1999a). Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 96: 5746–5751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu W, Orr-Urtreger A, Nigro F, Gelber S, Sutcliffe CB, Armstrong D et al. (1999b). Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4 subunits of neuronal nicotinic acetylcholine receptors. J Neurosci 19: 9298–9305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu X, Scott MM, Deneris ES . (2006). Shared long-range regulatory elements coordinate expression of a gene cluster encoding nicotinic receptor heteromeric subtypes. Mol Cell Biol 26: 5636–5649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Fyodorov D, Deneris ES . (1995). Transcriptional analysis of acetylcholine receptor alpha 3 gene promoter motifs that bind Sp1 and AP2. J Biol Chem 270: 8514–8520.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, McDonough J, Fyodorov D, Morris M, Wang F, Deneris ES . (1994). Characterization of an acetylcholine receptor alpha 3 gene promoter and its activation by the POU domain factor SCIP/Tst-1. J Biol Chem 269: 10252–10264.

    CAS  PubMed  Google Scholar 

  • Ye YN, Liu ES, Shin VY, Wu WK, Luo JC, Cho CH . (2004). Nicotine promoted colon cancer growth via epidermal growth factor receptor, c-Src, and 5-lipoxygenase-mediated signal pathway. J Pharmacol Exp Ther 308: 66–72.

    Article  CAS  PubMed  Google Scholar 

  • Zeidler R, Albermann K, Lang S . (2007). Nicotine and apoptosis. Apoptosis 12: 1927–1943.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Tang X, Zhang ZF, Velikina R, Shi S, Le AD . (2007). Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways. Clin Cancer Res 13: 4686–4694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng Y, Ritzenthaler JD, Roman J, Han S . (2007). Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression. Am J Respir Cell Mol Biol 37: 681–690.

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Deneris E, Zigmond RE . (1998). Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol 34: 164–178.

    Article  CAS  PubMed  Google Scholar 

  • Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA et al. (2003). Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 4: 191–196.

    Article  CAS  PubMed  Google Scholar 

  • Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C . (2002). Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J Neurosci 22: 8785–8789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors’ laboratories is supported in part by grants NS030243 (PDG) and AA017656 (ART) from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P D Gardner.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Improgo, M., Scofield, M., Tapper, A. et al. From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene 29, 4874–4884 (2010). https://doi.org/10.1038/onc.2010.256

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.256

Keywords

This article is cited by

Search

Quick links