p38 and EGF receptor kinase-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway is required for Zn2+-induced cyclooxygenase-2 expression
- PMID:15980035
- DOI: 10.1152/ajplung.00197.2005
p38 and EGF receptor kinase-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway is required for Zn2+-induced cyclooxygenase-2 expression
Abstract
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.
Similar articles
- Cigarette smoke extract induces COX-2 expression via a PKCalpha/c-Src/EGFR, PDGFR/PI3K/Akt/NF-kappaB pathway and p300 in tracheal smooth muscle cells.Yang CM, Lee IT, Lin CC, Yang YL, Luo SF, Kou YR, Hsiao LD.Yang CM, et al.Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L892-902. doi: 10.1152/ajplung.00151.2009. Epub 2009 Aug 28.Am J Physiol Lung Cell Mol Physiol. 2009.PMID:19717552
- Involvement of PI3K/Akt and p38 MAPK in the induction of COX-2 expression by bacterial lipopolysaccharide in murine adrenocortical cells.Mercau ME, Astort F, Giordanino EF, Martinez Calejman C, Sanchez R, Caldareri L, Repetto EM, Coso OA, Cymeryng CB.Mercau ME, et al.Mol Cell Endocrinol. 2014 Mar 25;384(1-2):43-51. doi: 10.1016/j.mce.2014.01.007. Epub 2014 Jan 11.Mol Cell Endocrinol. 2014.PMID:24424443
- EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes.Tung WH, Lee IT, Hsieh HL, Yang CM.Tung WH, et al.J Cell Physiol. 2010 Aug;224(2):376-86. doi: 10.1002/jcp.22133.J Cell Physiol. 2010.PMID:20333648
- Protein kinases as targets for developing anticancer agents from marine organisms.Qiao G, Bi K, Liu J, Cao S, Liu M, Pešić M, Lin X.Qiao G, et al.Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129759. doi: 10.1016/j.bbagen.2020.129759. Epub 2020 Oct 8.Biochim Biophys Acta Gen Subj. 2021.PMID:33038451Review.
- Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence.Xu Y, Li N, Xiang R, Sun P.Xu Y, et al.Trends Biochem Sci. 2014 Jun;39(6):268-76. doi: 10.1016/j.tibs.2014.04.004. Epub 2014 May 9.Trends Biochem Sci. 2014.PMID:24818748Free PMC article.Review.
Cited by
- NFAT3 is required for EGF-induced COX-2 transcription, but neither iNOS transcription nor cell transformation in Cl 41 cells.Li J, Lu H, Huang C.Li J, et al.Mol Cell Biochem. 2006 Sep;289(1-2):73-82. doi: 10.1007/s11010-006-9149-z. Epub 2006 May 23.Mol Cell Biochem. 2006.PMID:16718377
- Involvement of mitogen-activated protein kinases and NFkappaB in LPS-induced CD40 expression on human monocytic cells.Wu W, Alexis NE, Chen X, Bromberg PA, Peden DB.Wu W, et al.Toxicol Appl Pharmacol. 2008 Apr 15;228(2):135-43. doi: 10.1016/j.taap.2007.12.002. Epub 2007 Dec 14.Toxicol Appl Pharmacol. 2008.PMID:18187173Free PMC article.
- Zinc Signaling in the Mammary Gland: For Better and for Worse.Chakraborty M, Hershfinkel M.Chakraborty M, et al.Biomedicines. 2021 Sep 12;9(9):1204. doi: 10.3390/biomedicines9091204.Biomedicines. 2021.PMID:34572390Free PMC article.Review.
- Obestatin controls skeletal muscle fiber-type determination.Santos-Zas I, Cid-Díaz T, González-Sánchez J, Gurriarán-Rodriguez U, Seoane-Mosteiro C, Porteiro B, Nogueiras R, Casabiell X, Relova JL, Gallego R, Mouly V, Pazos Y, Camiña JP.Santos-Zas I, et al.Sci Rep. 2017 May 18;7(1):2137. doi: 10.1038/s41598-017-02337-4.Sci Rep. 2017.PMID:28522824Free PMC article.
- Non-redox cycling mechanisms of oxidative stress induced by PM metals.Samet JM, Chen H, Pennington ER, Bromberg PA.Samet JM, et al.Free Radic Biol Med. 2020 May 1;151:26-37. doi: 10.1016/j.freeradbiomed.2019.12.027. Epub 2019 Dec 23.Free Radic Biol Med. 2020.PMID:31877355Free PMC article.Review.
Publication types
MeSH terms
Substances
Related information
Grants and funding
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous