Zinc-induced PTEN Protein Degradation through the Proteasome Pathway in Human Airway Epithelial Cells

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  • Wu, Weidong
    • University of North Carolina at Chapel Hill
  • Wang, Xinchao
    • University of North Carolina at Chapel Hill
  • Zhang, Wenli
    • University of North Carolina at Chapel Hill
  • Reed, William
    • University of North Carolina at Chapel Hill
  • Samet, James M.
    • Other Affiliation: US EPA National Health and Environmental Effects Research Laboratory
  • Whang, Young E.
    • University of North Carolina at Chapel Hill
  • Ghio, Andrew J.
    • Other Affiliation: US EPA National Health and Environmental Effects Research Laboratory
Abstract
  • The tumor suppressor PTEN is a putative negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. Exposure to Zn2+ ions induces Akt activation, suggesting that PTEN may be modulated in this process. Therefore, the effects of Zn2+ on PTEN were studied in human airway epithelial cells and rat lungs. Treatment with Zn2+ resulted in a significant reduction in levels of PTEN protein in a dose- and time-dependent fashion in a human airway epithelial cell line. This effect of Zn2+was also observed in normal human airway epithelial cells in primary culture and in rat airway epithelium in vivo. Concomitantly, levels of PTEN mRNA were also significantly reduced by Zn2+ exposure. PTEN phosphatase activity evaluated by measuring Akt phosphorylation decreased after Zn2+ treatment. Pretreatment of the cells with a proteasome inhibitor significantly blocked zinc-induced reduction of PTEN protein as well as the increase in Akt phosphorylation, implicating the involvement of proteasome-mediated PTEN degradation. Further study revealed that Zn2+-induced ubiquitination of PTEN protein may mediate this process. A phosphatidylinositol 3-kinase inhibitor blocked PTEN degradation induced by Zn2+, suggesting that phosphatidylinositol 3-kinase may participate in the regulation of PTEN. However, both the proteasome inhibitor and phosphatidylinositol 3-kinase inhibitor failed to prevent significant down-regulation of PTEN mRNA expression in response to Zn2+. In summary, exposure to Zn2+ ions causes PTEN degradation and loss of function, which is mediated by an ubiquitin-associated proteolytic process in the airway epithelium.
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  • Article
Rights statement
  • In Copyright
Journal title
  • The Journal of Biological Chemistry
Journal volume
  • 278
Journal issue
  • 30
Page start
  • 28258
Page end
  • 28263
Language
  • English
ISSN
  • 0021-9258
  • 1083-351X

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