A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo.
A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo.
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DOI：
10.1083/jcb.200910006
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发表时间：
2010-06-14
期刊：
影响因子：
--
通讯作者：
Edgar BA
中科院分区：
文献类型：
--
作者：
Buttitta LA;Katzaroff AJ;Edgar BA
CycE和E2 F两者的过表达对于触发终末分化的翼细胞的细胞周期再进入和过度增殖是必需的。黑腹果蝇翅膀和眼睛中的终末分化细胞在E2 F或细胞周期蛋白E（CycE）的失调后很大程度上抵抗增殖，但两种因子一起的外源表达可以绕过细胞周期退出。在这项研究中，我们表明这是细胞周期控制机制合作的结果，限制E2 F-CycE正反馈，阻止终末分化后的循环。分化后异常的CycE活性导致E2 F激活复合物的降解，这增加了CycE抗性E2 F阻遏复合物的比例，导致稳定的E2 F靶基因阻遏。如果分化后E2 F依赖性抑制消失，则高后期促进复合物/环体（APC/C）活性会降解关键的E2 F靶点，以限制细胞周期重新进入。提供CycE和E2 F活性通过同时抑制APC/C和诱导分化后细胞周期重入所必需的一组E2 F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最终分化的细胞组成的组织生长。
Overexpression of both CycE and E2F is necessary to trigger cell cycle reentry and overproliferation of terminally differentiated wing cells. 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.
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