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ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN
Citation:
Wu, W., J M. Samet, P A. Bromberg, AND L. Graves. ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN. Presented at American Thoracic Society, Orlando, FL, May 21-26, 2004.
Description:
Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
*CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studies Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, NC 27711
RATIONALE: Mounting evidence indicates that Zn2+ contributes to ambient particulate matter-induced pulmonary inflammation. Reduced protein expression and activity of the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) was recently proposed to mediate airway hyperresponsiveness and inflammation. Zn2+ exposure results in PTEN degradation in a human bronchial epithelial cell line BEAS-2B. Therefore, the role of PTEN downregulation in Zn2+-induced expression of the gene for the pro-inflammatory protein cyclooxygenase-2 (COX-2) was examined in this study. METHODS: BEAS-2B cells were grown in growth factor-free medium prior to Zn2+ stimulation (50 ?M) for 8 h. Cells were treated with the proteasome inhibitor MG132, or were infected with titered adenoviruses to induce overexpression of wild-type PTEN (ad-wt-PTEN) or of dominant negative Akt (ad-dn-Akt) before exposure to Zn2+. Levels of COX-2 mRNA were measured using quantitative RT-PCR. RESULTS: Zn2+ exposure induced a marked increase in COX-2 expression in BEAS-2B cells. MG132, which was shown to block Zn2+-induced endogenous PTEN degradation, inhibited Zn2+-induced COX-2 expression. Overexpression of wt-PTEN blocked Zn2+-induced phosphorylation of Akt, a downstream signaling element in the PI3K pathway, as well as COX-2 expression. Overexpression of dn-Akt suppressed Zn2+-induced phosphorylation of GSK-3, a downstream kinase of Akt, and COX-2 expression, but showed only a minimal effect on the reduction of PTEN protein levels induced by Zn2+. CONCLUSIONS: PTEN antagonizes Zn2+-induced PI3K/Akt signaling pathway in BEAS-2B cells and thus PTEN modulation plays a pivotal role in Zn2+-induced COX-2 expression. This study was supported by U.S. EPA STAR grant R82921401-01 and Cooperative Agreement CR#829522 but does not necessarily reflect EPA policy.