Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
J Cell Biol. 2010 Jun 14;189(6):981-96. doi: 10.1083/jcb.200910006.
Terminally differentiated cells in Drosophila melanogaster wings and eyes are largely resistant to proliferation upon deregulation of either E2F or cyclin E (CycE), but exogenous expression of both factors together can bypass cell cycle exit. In this study, we show this is the result of cooperation of cell cycle control mechanisms that limit E2F-CycE positive feedback and prevent cycling after terminal differentiation. Aberrant CycE activity after differentiation leads to the degradation of E2F activator complexes, which increases the proportion of CycE-resistant E2F repressor complexes, resulting in stable E2F target gene repression. If E2F-dependent repression is lost after differentiation, high anaphase-promoting complex/cyclosome (APC/C) activity degrades key E2F targets to limit cell cycle reentry. Providing both CycE and E2F activities bypasses exit by simultaneously inhibiting the APC/C and inducing a group of E2F target genes essential for cell cycle reentry after differentiation. These mechanisms are essential for proper development, as evading them leads to tissue outgrowths composed of dividing but terminally differentiated cells.
在果蝇翅膀和眼睛的终末分化细胞中，E2F 或细胞周期蛋白 E（CycE）的失调在很大程度上阻止了细胞的增殖，但是这两种因子的外源表达可以绕过细胞周期退出。在这项研究中，我们表明，这是限制 E2F-CycE 正反馈并防止终末分化后细胞周期的细胞周期控制机制的合作结果。分化后异常的 CycE 活性导致 E2F 激活复合物的降解，从而增加了 CycE 抗性 E2F 抑制复合物的比例，从而导致 E2F 靶基因的稳定抑制。如果分化后 E2F 依赖性抑制丧失，则高有丝分裂促进复合物/细胞周期蛋白（APC/C）活性降解关键的 E2F 靶标，以限制细胞周期再进入。提供 CycE 和 E2F 活性可通过同时抑制 APC/C 并诱导一组分化后细胞周期再进入所必需的 E2F 靶基因来绕过退出。这些机制对于正常发育至关重要，因为逃避它们会导致由分裂但终末分化的细胞组成的组织过度生长。
