title: Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cells.
abstract: Epidemiological evidence suggests that cigarette smoke induces squamous metaplasia in human tracheobronchial epithelium that can progress to lung squamous carcinoma. But it is not well understood how tracheobronchial epithelial cells transduce the signals that mediate cigarette smoke-induced squamous differentiation or squamous metaplasia. In the present study, we found that in vitro cigarette smoke components notably inhibited glycogen synthase kinase 3 (GSK3) and induced the expression of involucrin, a marker of squamous differentiation. The inactivation of GSK3 by two highly selective inhibitors, lithium and SB216763, also significantly enhanced involucrin expression in cultured porcine tracheobronchial epithelial cells (PTBECs). Moreover, we demonstrated that cigarette smoke components significantly promoted activator protein-1 (AP-1) binding activities to the upstream regulatory region of involucrin gene, and similar results were observed by further studies through using GSK3 inhibitors to imitate the effects of cigarette smoke components. Taken together, we conclude that GSK3 is involved in involucrin expression induced by cigarette smoke in PTBEC probably via negatively regulating AP-1 activity, implying a possible mechanism responsible for squamous differentiation induced by cigarette smoke.
authors.affiliation: Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Pulmonary Disease of Ministry of Health of China, Wuhan 430030, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tian
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Wen-shu
authors.initials: WS
authors.lastname: Chen
authors.forename: Jian-Sha
authors.initials: JS
authors.lastname: Li
authors.forename: Ren-Liang
authors.initials: RL
authors.lastname: Wu
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D008679:Metaplasia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D013552:Swine; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011498:Protein Precursors; C417521:SB 216763; D012906:Smoke; D018808:Transcription Factor AP-1; C032253:involucrin; D008094:Lithium; D038362:Glycogen Synthase Kinase 3