Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro

Jia Luo; Yanbo Sun; Hong Lin; Yong Qian; Zheng Li; Stephen S Leonard; Chuanshu Huang; Xianglin Shi

doi:10.1074/jbc.M208295200

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Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro

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Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro

Jia Luo, Yanbo Sun, Hong Lin, Yong Qian, Zheng Li, Stephen S Leonard, Chuanshu Huang and Xianglin Shi

The Journal of biological chemistry, Vol.278(7), pp.4542-4551

02/14/2003

DOI: 10.1074/jbc.M208295200

PMID: 12454017

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Abstract

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.

Adaptor Proteins, Signal Transducing

Animals

Carrier Proteins - metabolism

Cells, Cultured

Central Nervous System Diseases - chemically induced

Central Nervous System Diseases - pathology

Cerebellum - cytology

Cerebellum - drug effects

Cerebellum - metabolism

fas Receptor - metabolism

Fas-Associated Death Domain Protein

Hazardous Substances - toxicity

JNK Mitogen-Activated Protein Kinases

MAP Kinase Kinase 4

MAP Kinase Signaling System - drug effects

Mitogen-Activated Protein Kinase Kinases - metabolism

Rats

Rats, Sprague-Dawley

Vanadates - toxicity

Details

Title: Subtitle: Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro
Creators: Jia Luo - West Virginia University
Yanbo Sun - West Virginia University
Hong Lin - West Virginia University
Yong Qian - National Institutes of Health
Zheng Li - West Virginia University
Stephen S Leonard - National Institutes of Health
Chuanshu Huang
Xianglin Shi - National Institutes of Health
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(7), pp.4542-4551
DOI: 10.1074/jbc.M208295200
PMID: 12454017
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: AA12968 / NIAAA NIH HHS CA90385 / NCI NIH HHS
Language: English
Date published: 02/14/2003
Academic Unit: Pathology
Record Identifier: 9984186427902771

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