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Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: a potential modulator of Fas-mediated apoptosis.

Authors
Lee, JK; Shin, JH; Suh, J; Choi, IS; Ryu, KS; Gwag, BJ
Citation
Neurobiology of disease, 30(2):174-185, 2008
Journal Title
Neurobiology of disease
ISSN
0969-99611095-953X
Abstract
Cortical neurons deprived of serum undergo apoptosis that is sensitive to inhibitors of macromolecule synthesis. Proteomic analysis revealed differential expression of 49 proteins in cortical neurons 8 h after serum deprivation. Tissue inhibitor of metalloproteinases-3 (TIMP-3), a pro-apoptotic protein in various cancer cells, was increased during serum deprivation-induced apoptosis (SDIA), but not during necrosis induced by excitotoxicity or oxidative stress. Levels of TIMP-3 were markedly increased in degenerating motor neurons in a transgenic model of familial amyotrophic lateral sclerosis. The TIMP-3 expression was accompanied by increase in Fas-FADD interaction, activated caspase-8, and caspase-3 during SDIA and in vulnerable spinal cord of the ALS mouse. SDIA and activation of the Fas pathway were prevented by addition of an active MMP-3. Timp-3 deletion by RNA interference attenuated SDIA in N2a cells. These findings provide evidence that TIMP-3 is an upstream mediator of neuronal apoptosis and likely contributes to neuronal loss in neurodegenerative diseases such as amyotrophic lateral sclerosis.
MeSH terms
Alanine/geneticsAmino Acid Substitution/geneticsAmyotrophic Lateral Sclerosis/enzymology*Amyotrophic Lateral Sclerosis/geneticsAnimalsAntigens, CD95/physiology*Apoptosis/drug effectsApoptosis/physiology*Cell Line, TumorCells, CulturedCulture Media, Serum-Free/pharmacology*Disease Models, AnimalFemaleGene Expression Regulation, Enzymologic/drug effectsGene Expression Regulation, Enzymologic/physiologyGlycine/geneticsHumansMaleMiceMice, Inbred C57BLMice, TransgenicNeurons/drug effectsNeurons/enzymology*Superoxide Dismutase/biosynthesisSuperoxide Dismutase/geneticsTissue Inhibitor of Metalloproteinase-3/biosynthesis*Tissue Inhibitor of Metalloproteinase-3/genetics*Tissue Inhibitor of Metalloproteinase-3/physiologyUp-Regulation/genetics*
DOI
10.1016/j.nbd.2008.01.004
PMID
18316197
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
곽, 병주
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