Liu D X, Greene L A
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Cell Tissue Res. 2001 Aug;305(2):217-28. doi: 10.1007/s004410100396.
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.
细胞凋亡是多细胞生物发育和组织稳态中的一个基本且重要的过程。在神经发生过程中产生的所有神经元中，约有一半在神经系统成熟之前通过凋亡死亡。细胞凋亡还与各种神经退行性疾病有关，如阿尔茨海默病和神经元损伤。对神经元凋亡潜在机制的研究导致了一个意外发现，即在许多情况下，静止和休眠的细胞周期机制的复苏是一个共同主题。最近的数据表明，细胞周期分子的不协调表达以及随之而来的细胞周期检查点的破坏可能是有丝分裂后神经元发生凋亡死亡的主要机制之一。证据表明，细胞周期蛋白D-CDK4/6活性的上调和E2F转录因子的失调是神经元凋亡早期阶段的关键事件。Rb家族成员对E2F的有效抑制是神经元存活所必需的。凋亡信号促进Rb家族成员的连续磷酸化和功能障碍，导致E2F的相继去抑制和选择性E2F反应基因的表达。因此，去抑制的E2F反应基因的表达可能有助于传播和放大凋亡信号，指导神经元细胞执行凋亡程序。
