Neuronal apoptosis induced by histone deacetylase inhibitors.
Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.
Salminen
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A
Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. antero.salminen@uku.fi
Tapiola
T
T
Korhonen
P
P
Suuronen
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors