A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium
Autor: | Daniel A, Linseman, Brandon J, Cornejo, Shoshona S, Le, Mary Kay, Meintzer, Tracey A, Laessig, Ron J, Bouchard, Kim A, Heidenreich |
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Rok vydání: | 2003 |
Předmět: |
Transcription
Genetic Calcineurin Inhibitors Apoptosis Lithium Rats Sprague-Dawley Glycogen Synthase Kinase 3 Animals Enzyme Inhibitors Phosphorylation Cells Cultured Neurons Glycogen Synthase Kinase 3 beta Caspase 3 MEF2 Transcription Factors Colforsin Phosphotransferases Blood Proteins DNA Caspase Inhibitors Rats DNA-Binding Proteins Enzyme Activation Myogenic Regulatory Factors Caspases Potassium Transcription Factors |
Zdroj: | Journal of neurochemistry. 85(6) |
ISSN: | 0022-3042 |
Popis: | Depolarization promotes the survival of cerebellar granule neurons via activation of the transcription factor myocyte enhancer factor 2D (MEF2D). Removal of depolarization induces hyperphosphorylation of MEF2D on serine/threonine residues, resulting in its decreased DNA binding and susceptibility to caspases. The subsequent loss of MEF2-dependent gene transcription contributes to the apoptosis of granule neurons. The kinase(s) that phosphorylates MEF2D during apoptosis is currently unknown. The serine/threonine kinase, glycogen synthase kinase-3 beta (GSK-3 beta), plays a pro-apoptotic role in granule neurons. To investigate a potential role for GSK-3 beta in MEF2D phosphorylation, we examined the effects of lithium, a non-competitive inhibitor of GSK-3 beta, on MEF2D activity in cultured cerebellar granule neurons. Lithium inhibited caspase-3 activation and chromatin condensation in granule neurons induced to undergo apoptosis by removal of depolarizing potassium and serum. Concurrently, lithium suppressed the hyperphosphorylation and caspase-mediated degradation of MEF2D. Moreover, lithium sustained MEF2 DNA binding and transcriptional activity in the absence of depolarization. Lithium also attenuated MEF2D hyperphosphorylation and apoptosis induced by calcineurin inhibition under depolarizing conditions, a GSK-3 beta-independent model of neuronal death. In contrast to lithium, MEF2D hyperphosphorylation was not inhibited by forskolin, insulin-like growth factor-I, or valproate, three mechanistically distinct inhibitors of GSK-3 beta. These results demonstrate that the kinase that phosphorylates and inhibits the pro-survival function of MEF2D in cerebellar granule neurons is a novel lithium target distinct from GSK-3 beta. |
Databáze: | OpenAIRE |
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