title: Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells.
abstract: Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pavan
authors.initials: P
authors.lastname: Adiseshaiah
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos / Q000502:physiology; D016758:Genes, jun / Q000502:physiology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity; D000099169:Fos-Related Antigen 1
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases; D020928:Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D012906:Smoke; D000099169:Fos-Related Antigen 1; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide