You are here:
P38 AND EGF RECEPTOR KINASE-MEDIATED ACTIVATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY IS REQUIRED FOR ZN2+INDUCED CYCLOOXYGENASE-2 EXPRESSION
Citation:
WU, W., R. A. SILBAJORIS, Y. E. WHANG, L. M. GRAVES, P. A. BROMBERG, AND J. M. SAMET. P38 AND EGF RECEPTOR KINASE-MEDIATED ACTIVATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY IS REQUIRED FOR ZN2+INDUCED CYCLOOXYGENASE-2 EXPRESSION. American Journal of Physiology - Lung Cellular and Molecular Physiology. American Physiological Society, Bethesda, MD, 289(5):L883-889, (2005).
Impact/Purpose:
This study aims to elucidate the role of intracellular signaling pathways in Zinc2+-induced Cyclooxygenase 2 expression in human bronchial epithelial cells
Description:
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.