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Redox regulates COX-2 upregulation and cell death in the neuronal response to cadmium

Authors
Journal
Cellular Signalling
0898-6568
Publisher
Elsevier
Publication Date
Volume
16
Issue
3
Identifiers
DOI: 10.1016/j.cellsig.2003.08.006
Keywords
  • Cadmium
  • Oxidative Stress
  • Reactive Oxygen Species
  • Cyclooxygenase-2
  • Caspase
  • Stress-Activated Kinases
Disciplines
  • Biology

Abstract

Abstract We reported previously that cadmium, an oxidative stressor, induced cyclooxygenase-2 (COX-2) upregulation in mouse neuronal cells that culminated in cell death. Herein, we show that cadmium induces reactive oxygen species (ROS) that activate c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) and their substrates, activating transcription factor 2 (ATF-2), CRE-binding protein (CREB) and c-Jun. This response is accompanied by induction of heme-oxygenase-1 (HO-1), poly(ADP-ribose) polymerase cleavage and a caspase-independent cell death. Inhibition of p38 MAPK, but not JNK, suppressed COX-2 protein expression and the cytotoxic response induced by cadmium. Selective inhibitors of phosphatidylinositol-3-kinase (PI3-K), LY294002, and flavoproteins, dipheneylene iodonium chloride (DPI), attenuated cadmium-induced ROS and stress kinase activation, suggesting that ROS can signal the COX-2 upregulation and neuronal cell death mediated by p38 MAPK. Collectively, these findings implicate PI3-K, a flavoprotein, p38 MAPK and COX-2 in a neuronal redox-regulated pathway that mediates cadmium-induced oxidative stress.

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