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The Journal of Neuroscience, May 11, 2005, 25(19):4823-4834; doi:10.1523/JNEUROSCI.1331-05.2005

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Cellular/Molecular
Cyclin-Dependent Kinase 5 Mediates Neurotoxin-Induced Degradation of the Transcription Factor Myocyte Enhancer Factor 2

Xiaoli Tang,^1 * Xuemin Wang,^1 * Xiaoming Gong,¹ Ming Tong,¹ David Park,² Zhengui Xia,³ and Zixu Mao¹

¹Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903, ²Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, and ³Departments of Environmental and Occupational Health Sciences and Pharmacology, University of Washington, Seattle, Washington 98195

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.

Key words: Cdk5; MEF2; neuronal apoptosis; neurotoxicity; transcription factor; caspase

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Received April 19, 2004; accepted April 7, 2005.

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