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Activation of JNK by vanadate induces a Fas-associated death domain (FADD)- dependent death of cerebellar granule progenitors in vitro.
Luo-J; Sun-Y; Lin-H; Qian-Y; Li-Z; Leonard-SS; Huang-C; Shi-X
J Biol Chem 2003 Feb; 278(7):4542-4551
Apoptosis is a highly regulated process that plays a critical role in neuronal development as well as the homeostasis of the adult nervous system. Vanadate, an environmental toxicant, causes developmental defects in the central nervous system. Here, we demonstrated that vanadate induced apoptosis in cultured cerebellar granule progenitors (CGPs). Treatment of cultured CGPs with vanadate activated ERKs and JNKs but not p38 MAPK and also induced c-Jun phosphorylation. In addition, vanadate induced FasL production, Fas (CD95) aggregation, and its association with the Fas-associated death domain (FADD), as well as the activation of caspase-8. Furthermore, vanadate generated reactive oxygen species (ROS) in CGPs; however, ROS was not involved in vanadate-mediated MAPK activation. Vanadate-induced FasL expression was ROS-dependent but JNK-independent. In contrast, vanadate-elicited Fas aggregation and Fas-FADD association, as well as caspase-8 activation, were dependent on JNK activation but were minimally regulated by ROS generation. The hydrogen peroxide scavenger, catalase, blocked vanadate-induced FasL expression and partially mitigated vanadate-induced cell death. On the other hand, dominant negative FADD and caspase-8 inhibitor completely eliminated vanadate-induced apoptosis. Thus, JNK signaling plays a major role in vanadate-mediated activation of the Fas-FADD-caspase-8 pathway that accounts for vanadate-induced apoptosis of CGPs.
In-vitro-studies; In-vitro-study; Nervous-system; Toxins; Cell-damage; Diseases; Proteins; Vanadium-compounds
Jia Luo, Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Science Center, Morgantown, West Virginia 26506
Issue of Publication
Journal of Biological Chemistry
Page last reviewed: April 12, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division