Cdk5 nuclear localization is p27-dependent in nerve cells: implications for cell cycle suppression and caspase-3 activation.
Initiation of a cell cycle in an adult neuron leads to cell death, placing great importance on the mechanisms that normally suppress the neuronal cell cycle. We have previously shown that the cyclin-dependent kinase Cdk5 is an important part of this process, but only when it is present in the nucleus. We report here that Cdk5 nuclear localization relies on its binding to the cyclin-dependent kinase inhibitor p27. Cdk5 has no intrinsic nuclear localization signal; in the absence of p27, two weak nuclear export signals that bind CRM1 cause it to shuttle to the cytoplasm. When a neuron is subjected to stress, such as exposure to beta-amyloid, the Cdk5-p27 interaction is lost, reducing Cdk5 levels in the nucleus and depriving the neuron of a major cell cycle suppression mechanism. Caspase-3 is activated within hours, but death is not immediate; elevated levels of cytoplasmic Cdk5 appear to retard neuronal death by a mechanism that may involve Bcl2. These data suggest a model in which Cdk5 exerts a double protective function in neurons: chronically suppressing the cell cycle when located in the nucleus and transiently delaying cell death in the cytoplasm.
Zhang
Jie
J
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8082, USA.
Li
Huifang
H
Herrup
Karl
K
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; 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; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
D016229:Amyloid beta-Peptides; C493961:Cdkn1b protein, mouse; D019913:Nuclear Localization Signals; D019253:Proto-Oncogene Proteins c-bcl-2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3