TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3.

Content Provider	Semantic Scholar
Author	Jurewicz, Anna Matysiak, Mariola Tybor, Krzysztof
Copyright Year	2003
Abstract	Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://brain.oxfordjournals.org/content/126/6/1358.full.pdf
Alternate Webpage(s)	http://brain.oxfordjournals.org/content/early/2003/05/06/brain.awg146.full.pdf
Alternate Webpage(s)	http://brain.oxfordjournals.org/content/brain/126/6/1358.full.pdf
Alternate Webpage(s)	https://pdfs.semanticscholar.org/454a/abd6c78828931244ef27f4a81a5ef1a368fd.pdf
PubMed reference number	12764057v1
Volume Number	126
Part	6
Journal	Brain : a journal of neurology
Language	English
Access Restriction	Open
Subject Keyword	Apoptosis Cell Death Cessation of life Dominant-Negative Mutation JUN gene MAP kinase kinase kinase activity Membrane Potentials Mitochondrial Membranes Mitogen-Activated Protein Kinases Mitogens Multiple Sclerosis Neoplasms Oligodendroglia Tumor Necrosis Factors transduction
Content Type	Text
Resource Type	Article