title: Cdk5-mediated inhibition of APC/C-Cdh1 switches on the cyclin D1-Cdk4-pRb pathway causing aberrant S-phase entry of postmitotic neurons.
abstract: The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation. Conversely, pharmacological or genetic inhibition of Cdk5 promotes Cdh1 ubiquitination and proteasomal degradation. Furthermore, we show that Cdk5-mediated phosphorylation and inactivation of Cdh1 leads to p27 depletion, which switches on the cyclin D1-cyclin-dependent kinase-4 (Cdk4)-retinoblastoma protein (pRb) pathway to allow the S-phase entry of neurons. However, neurons do not proceed through the cell cycle and die by apoptosis. These results indicate that APC/C-Cdh1 actively suppresses an aberrant cell cycle entry and death of neurons, highlighting its critical function in neuroprotection.
authors.affiliation: Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca - University of Salamanca, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics (IBFG), University of Salamanca - CSIC, 37007 Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Veas-Pérez de Tudela
authors.affiliation: Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca - University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Maestre
authors.affiliation: Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca - University of Salamanca, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics (IBFG), University of Salamanca - CSIC, 37007 Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Delgado-Esteban
authors.affiliation: Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca - University of Salamanca, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics (IBFG), University of Salamanca - CSIC, 37007 Salamanca, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
authors.affiliation: Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca - University of Salamanca, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics (IBFG), University of Salamanca - CSIC, 37007 Salamanca, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Almeida
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018698:Glutamic Acid; D008938:Mitosis; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D015398:Signal Transduction
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018698:Glutamic Acid; D051360:Cyclin-Dependent Kinase 5; D053148:Caspase 3