Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 19, Pages 4823-4834Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1331-05.2005
Keywords
Cdk5; MEF2; neuronal apoptosis; neurotoxicity; transcription factor; caspase
Categories
Funding
- NIA NIH HHS [AG023695, AG19193] Funding Source: Medline
- NICHD NIH HHS [HD39446] Funding Source: Medline
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Regulation of the process of neuronal death plays a central role both during development of the CNS and in adult brain. The transcription factor myocyte enhancer factor 2 ( MEF2) plays a critical role in neuronal survival. Cyclin- dependent kinase 5 ( Cdk5) mediates neurotoxic effects by phosphorylating and inhibiting MEF2. How Cdk5- dependent phosphorylation reduces MEF2 transactivation activity remained unknown. Here, we demonstrate a novel mechanism by which Cdk5, in conjunction with caspase, inhibits MEF2. Using primary cerebellar granule neuron as a model, our investigation reveals that neurotoxicity induces destabilization of MEF2s in neurons. Destabilization of MEF2 is caused by an increase in caspase- dependent cleavage of MEF2. This cleavage event requires nuclear activation of Cdk5 activity. Phosphorylation by Cdk5 alone is sufficient to promote degradation of MEF2A and MEF2D by caspase- 3. In contrast to MEF2A and MEF2D, MEF2C is not phosphorylated by Cdk5 after glutamate exposure and, therefore, resistant to neurotoxin- induced caspase-dependent degradation. Consistently, blocking Cdk5 or enhancing MEF2 reduced toxin- induced apoptosis. These findings define an important regulatory mechanism that for the first time links prodeath activities of Cdk5 and caspase. The convergence of Cdk5 phosphorylation- dependent caspase- mediated degradation of nuclear survival factors exemplified by MEF2 may represent a general process applicable to the regulation of other survival factors under diverse neurotoxic conditions.
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