Abstract
We describe a group of small-molecule inhibitors of Jun kinase (JNK)-dependent apoptosis. AEG3482, the parental compound, was identified in a screening effort designed to detect compounds that reduce apoptosis of neonatal sympathetic neurons after NGF withdrawal. We show that AEG3482 blocks apoptosis induced by the p75 neurotrophin receptor (p75NTR) or its cytosolic interactor, NRAGE, and demonstrate that AEG3482 blocks proapoptotic JNK activity. We show that AEG3482 induces production of heat shock protein 70 (HSP70), an endogenous inhibitor of JNK, and establish that HSP70 accumulation is required for the AEG3482-induced JNK blockade. We show that AEG3482 binds HSP90 and induces HSF1-dependent HSP70 mRNA expression and find that AEG3482 facilitates HSP70 production while retaining HSP90 chaperone activity. These studies establish that AEG3482 inhibits JNK activation and apoptosis by a mechanism involving induced expression of HSP proteins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / physiology
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Apoptosis / drug effects*
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Benzoquinones
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Enzyme Activation
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Enzyme Inhibitors / pharmacology*
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HSP70 Heat-Shock Proteins / biosynthesis*
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lactams, Macrocyclic
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology
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Neurons / cytology
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Neurons / drug effects
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PC12 Cells
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Phosphorylation
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Quinones / pharmacology
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Rats
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Receptor, Nerve Growth Factor / antagonists & inhibitors
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Receptor, Nerve Growth Factor / physiology
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Sulfonamides / pharmacology*
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Thiadiazoles / pharmacology*
Substances
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AEG 3482
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Antigens, Neoplasm
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Benzoquinones
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Enzyme Inhibitors
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HSP70 Heat-Shock Proteins
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Lactams, Macrocyclic
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MAGED1 protein, human
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Neoplasm Proteins
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Quinones
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Receptor, Nerve Growth Factor
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Sulfonamides
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Thiadiazoles
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JNK Mitogen-Activated Protein Kinases
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geldanamycin