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 - PubMed (original) (raw)
. 2006 Oct;20(12):2093-101.
doi: 10.1096/fj.06-6191com.
Affiliations
- PMID: 17012261
- DOI: 10.1096/fj.06-6191com
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
Juan Arredondo et al. FASEB J. 2006 Oct.
Abstract
The use of tobacco products is associated with an increased incidence of periodontal disease, poor response to periodontal therapy, and a high risk for developing head and neck cancer. Nicotine and tobacco-derived nitrosamines have been shown to exhibit their pathobiologic effects due in part to activation of the nicotinic acetylcholine (ACh) receptors (nAChRs), mainly alpha7 nAChR, expressed by oral keratinocytes (KCs). This study was designed to gain mechanistic insight into alpha7-mediated morbidity of tobacco products in the oral cavity. We investigated the signaling pathways downstream of alpha7 nAChR in monolayers of oral KCs exposed for 24 h to aged and diluted sidestream cigarette smoke (ADSS) or an equivalent concentration of pure nicotine. By both real-time polymerase chain reaction (PCR) and In-cell Western, the KCs stimulated with ADSS or nicotine showed multifold increases of STAT-3. These effects could be completely blocked or significantly (P<0.05) diminished if the cells were pretreated with the alpha7 antagonist alpha-bungarotoxin (alphaBTX) or transfected with anti-alpha7 small interfering RNA (siRNA-alpha7). The use of pathway inhibitors revealed that signaling through the Ras/Raf-1/MEK1/ERK steps mediated alpha7-dependent up-regulation of STAT-3. Targeted mutation of the alpha7 gene prevented ERK1/2 activation by nicotine. Using the gel mobility shift assay, we demonstrated that an increased protein binding activity of STAT-3 caused by ADSS or pure nicotine was mediated by janus-activated kinase (JAK)-2. Activation of JAK-2/STAT-3 pathway could be prevented by alphaBTX or siRNA-alpha7. Thus, nuclear transactivation of STAT-3 in KCs exposed to tobacco products is mediated via intracellular signaling downstream from alpha7, which proceeds via two complementary pathways. The Ras/Raf-1/MEK1/ERK cascade culminates in up-regulated expression of the gene encoding STAT-3, whereas recruitment and activation of tyrosine kinase JAK-2 phosphorylates it. Elucidation of this novel mechanism of nicotine-dependent nuclear transactivation of STAT-3 identifies oral alpha7 nAChR as a promising molecular target to prevent, reverse, or retard tobacco-related periodontal disease and progression of head and neck cancer by receptor inhibitors.
Similar articles
- Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytes.
Arredondo J, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA. Arredondo J, et al. Life Sci. 2007 May 30;80(24-25):2191-4. doi: 10.1016/j.lfs.2007.01.013. Epub 2007 Jan 17. Life Sci. 2007. PMID: 17291542 Free PMC article. - Receptor-mediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells.
Arredondo J, Chernyavsky AI, Marubio LM, Beaudet AL, Jolkovsky DL, Pinkerton KE, Grando SA. Arredondo J, et al. Am J Pathol. 2005 Feb;166(2):597-613. doi: 10.1016/s0002-9440(10)62281-x. Am J Pathol. 2005. PMID: 15681842 Free PMC article. - Depressing time: Waiting, melancholia, and the psychoanalytic practice of care.
Salisbury L, Baraitser L. Salisbury L, et al. In: Kirtsoglou E, Simpson B, editors. The Time of Anthropology: Studies of Contemporary Chronopolitics. Abingdon: Routledge; 2020. Chapter 5. In: Kirtsoglou E, Simpson B, editors. The Time of Anthropology: Studies of Contemporary Chronopolitics. Abingdon: Routledge; 2020. Chapter 5. PMID: 36137063 Free Books & Documents. Review. - Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers.
Schaal C, Chellappan SP. Schaal C, et al. Mol Cancer Res. 2014 Jan;12(1):14-23. doi: 10.1158/1541-7786.MCR-13-0541. Epub 2014 Jan 7. Mol Cancer Res. 2014. PMID: 24398389 Free PMC article. Review.
Cited by
- Mechanisms of E-Cigarette Vape-Induced Epithelial Cell Damage.
Auschwitz E, Almeda J, Andl CD. Auschwitz E, et al. Cells. 2023 Oct 31;12(21):2552. doi: 10.3390/cells12212552. Cells. 2023. PMID: 37947630 Free PMC article. Review. - A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression.
Costantini TW, Dang X, Yurchyshyna MV, Coimbra R, Eliceiri BP, Baird A. Costantini TW, et al. Mol Med. 2015 Apr 3;21(1):323-36. doi: 10.2119/molmed.2015.00018. Mol Med. 2015. PMID: 25860877 Free PMC article. - Nicotine overrides DNA damage-induced G1/S restriction in lung cells.
Nishioka T, Yamamoto D, Zhu T, Guo J, Kim SH, Chen CY. Nishioka T, et al. PLoS One. 2011 Apr 29;6(4):e18619. doi: 10.1371/journal.pone.0018619. PLoS One. 2011. PMID: 21559516 Free PMC article. - Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection.
Buckingham SD, Jones AK, Brown LA, Sattelle DB. Buckingham SD, et al. Pharmacol Rev. 2009 Mar;61(1):39-61. doi: 10.1124/pr.108.000562. Epub 2009 Mar 16. Pharmacol Rev. 2009. PMID: 19293145 Free PMC article. Review. - Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis.
Kumar AS, Jagadeeshan S, Pitani RS, Ramshankar V, Venkitasamy K, Venkatraman G, Rayala SK. Kumar AS, et al. Mol Cell Biol. 2017 Mar 1;37(6):e00510-16. doi: 10.1128/MCB.00510-16. Print 2017 Mar 15. Mol Cell Biol. 2017. PMID: 27956702 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous