p38 and EGF receptor kinase-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway is required for Zn2+-induced cyclooxygenase-2 expression.
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 phosphatase and tensin homolog deleted on chromosome 10, 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 NH2-terminal kinase and the extracellular signal-regulated kinases have minimal effect on Akt phosphorylation and COX-2 expression. Inhibition of p38, Src, and EGFR 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 EGFR kinase-mediated Akt activation is required for Zn2+-induced COX-2 expression and that the PI3K/Akt signaling pathway plays a central role in this event.
Wu
Weidong
W
Division of Immunology and Infectious Disease, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA. Weidong_Wu@med.unc.edu
Silbajoris
Robert A
RA
Whang
Young E
YE
Graves
Lee M
LM
Bromberg
Philip A
PA
Samet
James M
JM
D001483:Base Sequence; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015032:Zinc / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D018076:DNA, Complementary; D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc