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Mixed lineage kinase 3 mediates gp120IIIB‐induced neurotoxicity
Author(s) -
Bodner Amos,
Maroney Anna C.,
Finn James P.,
Ghadge Ghanashyam,
Roos Raymond,
Miller Richard J.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01088.x
Subject(s) - neurotoxicity , hippocampal formation , apoptosis , biology , activator (genetics) , programmed cell death , microbiology and biotechnology , kinase , protein kinase a , cancer research , neuroscience , chemistry , biochemistry , toxicity , receptor , organic chemistry
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.