期刊
BIOCHEMICAL JOURNAL
卷 416, 期 -, 页码 395-405出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20080775
关键词
apoptosis; calcium; calpain; endoplasmic reticulum stress; gene regulation; paraoxonase
资金
- Deutsche Forschungsgemeinschaft Collaborative Research Center 553 [A1]
- Faculty of Medicine, Johannes Gutenberg University, Mainz
PON2 (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 Ca2+ 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 Ca2+-dependent active degradation of PON2 mRNA, elicited by its 5'-untranslated region. In addition, thapsigargin and A23187 also induced PON2 protein degradation by a Ca2+-dependent calpain-mediated mechanism. Thus we provide evidence that independent mechanisms mediate the degradation of PON2 mRNA and protein after disturbance of Ca2+ homoeostasis. Furthermore, because Ca2+-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.
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