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lüll Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis Horke S; Witte I; Wilgenbus P; Altenhofer S; Kruger M; Li H; Forstermann UBiochem J 2008[Dec]; 416 (3): 395-405PON2 (paraoxonase-2) is a ubiquitously expressed antioxidative protein which is largely found in the ER (endoplasmic reticulum). Addressing the cytoprotective functions of PON2, we observed that PON2 overexpression provided significant resistance to ER-stress-induced caspase 3 activation when the ER stress was induced by interference with protein modification (by tunicamycin or dithiothreitol), but not when ER stress was induced by disturbance of Ca(2+) homoeostasis (by thapsigargin or A23187). When analysing the underlying molecular events, we found an activation of the PON2 promoter in response to all tested ER-stress-inducing stimuli. However, only tunicamycin and dithiothreitol resulted in increased PON2 mRNA and protein levels. In contrast, when ER stress was caused by thapsigargin or A23187, we observed a Ca(2+)-dependent active degradation of PON2 mRNA, elicited by its 5'-untranslated region. In addition, thapsigargin and A23187 also induced PON2 protein degradation by a Ca(2+)-dependent calpain-mediated mechanism. Thus we provide evidence that independent mechanisms mediate the degradation of PON2 mRNA and protein after disturbance of Ca(2+) homoeostasis. Furthermore, because Ca(2+)-disturbance induces ER stress, but abrogates the otherwise protective function of PON2 against ER-stress-induced apoptosis, we propose that the underlying cause of ER stress determines the efficacy of putative cellular defence mechanisms.|*Homeostasis[MESH]|*Stress, Physiological[MESH]|3' Untranslated Regions[MESH]|5' Untranslated Regions[MESH]|Apoptosis/*physiology[MESH]|Aryldialkylphosphatase/genetics/*metabolism[MESH]|Calcimycin/pharmacology[MESH]|Calcium/*metabolism[MESH]|Calpain/metabolism[MESH]|Cell Line[MESH]|Dithiothreitol/pharmacology[MESH]|Endoplasmic Reticulum/drug effects/*enzymology/*physiology[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Gene Expression Regulation, Enzymologic[MESH]|Humans[MESH]|Ionophores/pharmacology[MESH]|Promoter Regions, Genetic[MESH]|RNA Stability[MESH]|Thapsigargin/pharmacology[MESH]|Tunicamycin/pharmacology[MESH] |