Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK.
In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFR-independent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK.
Gensch
Erin
E
Department of Anatomy, Cardiovascular Research Institute and Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143, USA.
Gallup
Marianne
M
Sucher
Anatol
A
Li
Daizong
D
Gebremichael
Assefa
A
Lemjabbar
Hassan
H
Mengistab
Aklilu
A
Dasari
Vijay
V
Hotchkiss
Jon
J
Harkema
Jack
J
Basbaum
Carol
C
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D051921:Fos-Related Antigen-2; D017353:Gene Deletion; D005799:Genes, Dominant; D006801:Humans; D017403:In Situ Hybridization; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D008297:Male; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009077:Mucins / Q000378:metabolism*; D009154:Mutation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C497874:Fosl2 protein, rat; D009077:Mucins; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases