TY - JOUR T1 - Cyclin-Dependent Kinase 5 Mediates Neurotoxin-Induced Degradation of the Transcription Factor Myocyte Enhancer Factor 2 JF - The Journal of Neuroscience JO - J. Neurosci. SP - 4823 LP - 4834 DO - 10.1523/JNEUROSCI.1331-05.2005 VL - 25 IS - 19 AU - Xiaoli Tang AU - Xuemin Wang AU - Xiaoming Gong AU - Ming Tong AU - David Park AU - Zhengui Xia AU - Zixu Mao Y1 - 2005/05/11 UR - http://www.jneurosci.org/content/25/19/4823.abstract N2 - 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. ER -