Neuronal apoptosis at the G1/S cell cycle checkpoint.
Apoptosis is a fundamental and essential process in development and tissue homeostasis of multicellular organisms. Roughly half of all the neurons produced during neurogenesis die apoptotically before the nervous system matures. Apoptosis is also involved in various neurodegenerative disorders such as Alzheimer's disease and neuronal trauma. Investigation of the mechanisms underlying neuronal apoptosis led to an unexpected discovery that in many cases revival of the quiescent and dormant cell cycle machinery is a common theme. Recent data suggest that uncoordinated expression of cell cycle molecules and the consequent breach of cell cycle checkpoints could be one of the primary mechanisms by which postmitotic neurons undergo apoptotic death. Evidence indicates that upregulation of cyclin-D-CDK4/6 activity and deregulation of E2F transcription factors mark key events in early stages of neuronal apoptosis. Active E2F repression by Rb family members is required for the survival of neurons. Apoptotic signals promote successive phosphorylation and dysfunction of Rb family members, resulting in sequential E2F derepression and expression of selective E2F-responsive genes. Thus, expression of derepressed E2F-responsive genes may be instrumental in propagating and amplifying the apoptotic signals instructing neuronal cells to carry out the apoptotic program.
Liu
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DX
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. dl1345@columbia.edu
Greene
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LA
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016193:G1 Phase; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016196:S Phase; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C493837:RBL2 protein, human; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases