title: Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in post-mitotic neurons.
abstract: In a variety of neurodegenerative disease, despite the frequent correlation of neuronal cell cycle and cell death in the same neuronal populations, the mechanistic pathway linking the two remains undefined. One possible link is the atypical cyclin dependent kinase, Cdk5. Cdk5 exerts a double protective function in neurons, first by suppressing the cell cycle in the nucleus and second by suppressing cell death in the cytoplasm. Cdk5 transport between nucleus and cytoplasm serves to regulate the balance between these two events. Cdk5 nuclear localization relies on its interaction with p27, and its cell cycle suppression activity is achieved by direct binding to E2F1, disrupting the DP1-E2F1 dimer and its DNA binding ability. To bind to E2F1, Cdk5 does not need to be catalytically active but it does require a physical association with both p27 and its cyclin-like activator, p35. Because of this requirement, the proper levels and locations of p27 and p35 are characteristics that endow a neuron a unique form of cell cycle regulation that uses Cdk5 in a non-catalytic role. The findings offer cautionary notes to any strategy aimed at blocking Cdk5 activity as a means of combating neurodegenerative disease. To the extent that these approaches either directly or indirectly influence Cdk5 levels or location, they may produce unexpected and possibly unwanted consequences.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002453:Cell Cycle; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D050680:Transcription Factor DP1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D009419:Nerve Tissue Proteins; C493736:Tfdp1 protein, mouse; D050680:Transcription Factor DP1; C089495:neuronal Cdk5 activator (p25-p35); D050760:Cyclin-Dependent Kinase Inhibitor p27; D051360:Cyclin-Dependent Kinase 5