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1 Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA; Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, nc, USA
2 Human Studies Division, United State Environmental Protection Agency, RTP, NC, USA
3 Department of Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, nc, USA
4 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA
5 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, nc, USA
* To whom correspondence should be addressed. E-mail: weidong_wu{at}med.unc.edu.
Cyclooxygenase 2 (COX-2) expression is induced by physiological and inflammatory stimuli. Regulation of COX-2 expression is stimulus- and cell type-specific. Exposure to Zn2+ has been associated with activation of multiple intracellular signaling pathways as well as the induction of COX-2 expression. This study aims to elucidate the role of intracellular signaling pathways in Zn2+-induced COX-2 expression in human bronchial epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) potently block Zn2+-induced COX-2 mRNA and protein expression. Overexpression of adenoviral constructs encoding dominant-negative Akt kinase downstream of PI3K or wild-type PTEN, an important PI3K phosphatase, suppresses COX-2 mRNA expression induced by Zn2+. Zn2+ exposure induces phosphorylation of the tyrosine kinases including Src and EGF receptor (EGFR), and the p38 mitogen-activated protein kinase. Blockage of these kinases results in inhibition of Zn2+-induced Akt phosphorylation as well as COX-2 protein expression. Overexpression of dominant negative p38 constructs suppresses Zn2+-induced increase in COX-2 promoter activity. In contrast, the c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated kinases (ERK) have minimal effect on Akt phosphorylation and COX-2 expression. Inhibition of p38, Src, and EGF receptor kinases with pharmacological inhibitors markedly reduces Akt phosphorylation induced by Zn2+. However, the PI3K inhibitors do not show inhibitory effects on p38, Src, and EGFR. These data suggest that p38 and EGF receptor kinase-mediated Akt activation is required for Zn2+-induced cyclooxygenase-2 expression and that the PI3K/Akt signaling pathway plays a central role in this event.
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