Mixed lineage kinase 3 mediates gp120IIIB-induced neurotoxicity.
Overexpression of gp120, the major coat protein of the HIV-1 virus, in central glial cells, or treatment of neurons with gp120 in culture, produces apoptotic neuronal death. Here we demonstrate that CEP-1347 (KT7515), an inhibitor of mixed lineage kinase 3 (MLK3), an upstream activator of JNK, inhibits gp120IIIB-induced apoptosis of hippocampal neurons. Furthermore, expression of wild type MLK3 in hippocampal pyramidal neurons enhanced gp120IIIB-induced neurotoxicity, whereas expression of a dominant negative MLK3 protected neurons from the toxic effects of the glycoprotein. These results indicate a role for MLK3 signaling in gp120IIIB-induced neuronal death, and suggest potential clinical utility of CEP-1347 in inhibiting the progression of AIDS dementia.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015704:CD4 Antigens / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D006624:Hippocampus; D007211:Indoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D015704:CD4 Antigens; D002227:Carbazoles; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D018696:Neuroprotective Agents; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C106592:3,9-bis((ethylthio)methyl)-K-252a