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

• Published in: The Journal of neuroscience Vol. 25; no. 19; pp. 4823 - 4834
• Main Authors: Tang, Xiaoli, Wang, Xuemin, Gong, Xiaoming, Tong, Ming, Park, David, Xia, Zhengui, Mao, Zixu
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 11.05.2005; Society for Neuroscience
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Animals; Animals, Newborn; Blotting, Western - methods; Caspase Inhibitors; Caspases - metabolism; Cell Count - methods; Cell Death - drug effects; Cells, Cultured; Cellular/Molecular; Cerebellum - cytology; Chromatin - drug effects; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Drug Interactions; Glutamic Acid - toxicity; Green Fluorescent Proteins - metabolism; Luciferases; MEF2 Transcription Factors; Myogenic Regulatory Factors - classification; Myogenic Regulatory Factors - genetics; Myogenic Regulatory Factors - metabolism; Neurons - drug effects; Neurons - metabolism; Neurotoxins - toxicity; Oligopeptides - pharmacology; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Rats; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Roscovitine; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; Time Factors; Transfection - methods
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1331-05.2005

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.