Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis.
Myocyte enhancer factor-2 (MEF2) transcription factors are activated by p38 mitogen-activated protein kinase during neuronal and myogenic differentiation. Recent work has shown that stimulation of this pathway is antiapoptotic during development but proapoptotic in mature neurons exposed to excitotoxic or other stress. We now report that excitotoxic (N-methyl-D-aspartate) insults to mature cerebrocortical neurons activate caspase-3, -7, in turn cleaving MEF2A, C, and D isoforms. MEF2 cleavage fragments containing a truncated transactivation domain but preserved DNA-binding domain block MEF2 transcriptional activity via dominant interference. Transfection of constitutively active MEF2 (MEF2C-CA) rescues MEF2 transcriptional activity after N-methyl-D-aspartate insult and prevents neuronal apoptosis. Conversely, dominant-interfering MEF2 abrogates neuroprotection by MEF2C-CA. These results define a pathway to excitotoxic neuronal stress/apoptosis via caspase-catalyzed cleavage of MEF2. Additionally, we show that similar MEF2 cleavage fragments are generated in vivo during focal stroke damage. Hence, this pathway appears to have pathophysiological relevance in vivo.
Okamoto
Shu-ichi
S
Center for Neuroscience and Aging, Apoptosis and Cell Death Research Program, The Burnham Institute, La Jolla, CA 92037, USA.
Li
Zhen
Z
Ju
Chung
C
Scholzke
Marion N
MN
Mathews
Emily
E
Cui
Jiankun
J
Salvesen
Guy S
GS
Bossy-Wetzel
Ella
E
Lipton
Stuart A
SA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018006:Myogenic Regulatory Factors; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D020218:Response Elements / Q000235:genetics; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D014157:Transcription Factors; D016202:N-Methylaspartate; D004247:DNA; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases