Julie A Unverferth

Saint Louis University, Сент-Луис, Michigan, United States

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Publications (1)8.1 Total impact

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    ABSTRACT: The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate beta-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced beta-cell death was examined. The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies. UPR activation correlates with beta-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokine-induced UPR activation and beta-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce beta-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by approximately 35% in tunicamycin-treated cells expressing an S51A eIF2 alpha mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2 alpha mutant affects the levels of cytokine-induced death. While cytokine-induced beta-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced beta-cell death.
    Diabetes 02/2008; 57(1):124-32. DOI:10.2337/db07-0944 · 8.10 Impact Factor

Publication Stats

49 Citations
8.10 Total Impact Points

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  • 2008
    • Saint Louis University
      • Department of Biochemistry & Molecular Biology
      Сент-Луис, Michigan, United States