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Published ahead of print on November 4, 2004, doi:10.1165/rcmb.2004-0198OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 1, January 2005, 72-81

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Submitted on June 21, 2004
Revised on November 4, 2004

MMP/EGFR/MAP kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells

Qin Zhang1, Pavan Adiseshaiah1, and Sekhar P Reddy2*

1 Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 2 Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: sreddy{at}jhsph.edu.

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 physiological and pathophysiological 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, EGFR-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of ERK, 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 MMP 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 MAP kinase signaling in controlling CS-induced fra-1 expression.




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