Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK

Erin Gensch, Marianne Gallup, Anatol Sucher, Daizong Li, Assefa Gebremichael, Hassan Lemjabbar, Aklilu Mengistab, Vijay Dasari, Jon Hotchkiss, Jack Harkema, Carol Basbaum
Journal of Biological Chemistry 2004 September 10, 279 (37): 39085-93
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.

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