S phase-coupled E2f1 destruction ensures homeostasis in proliferating tissues.
S phase-coupled E2f1 destruction ensures homeostasis in proliferating tissues.
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DOI：
10.1371/journal.pgen.1002831
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Duronio RJ
中科院分区：
文献类型：
--
作者：
Davidson JM;Duronio RJ
细胞周期调节因子的精确控制对于正常发育和组织稳态至关重要。 E2F转录因子在G1期间被激活以驱动G1-S转变，然后在S期期间被多种机制抑制。在这里，我们对单个果蝇激活剂 E2F (E2f1) 进行基因操作，以探索 S 期耦合 E2F 下调的发育要求。在 S 期未被破坏的 E2f1 突变体的表达驱动细胞周期进展并导致细胞凋亡。有趣的是，这种细胞凋亡并不完全是细胞周期进程不当的结果，因为不能充当转录因子或驱动细胞周期进程的稳定 E2f1 突变体也会引发细胞凋亡。这一观察结果表明，S 期 E2f1 蛋白的不适当存在可以通过独立于直接作用于靶基因的 E2F 的机制触发细胞凋亡。 S 期稳定的 E2f1 触发细胞凋亡的能力需要 E2f1 和果蝇 pRb 同源物 Rbf1 之间的相互作用，并涉及促凋亡基因 hid 的诱导。同时阻断 S 期 E2f1 破坏并抑制细胞凋亡的诱导会导致组织过度生长和致死。我们提出，S期E2f1蛋白的不适当积累会触发通过凋亡消除潜在的增生细胞，以确保快速增殖组织的正常发育。快速生长的组织为研究发育中生物体正常器官结构和功能所需的细胞增殖和细胞凋亡之间的仔细平衡提供了绝佳的机会。我们提供的证据表明，对于调节果蝇细胞周期进展至关重要的转录因子 E2f1 也可作为正常组织发育的指标。 E2f1 在细胞周期 G1 期激活，触发进入 S 期。然后，E2f1 活性在 S 期被一种将 E2f1 蛋白水解直接与 DNA 合成耦合的机制迅速抑制。在幼虫发育过程中，S 期稳定形式的 E2f1 表达会导致快速增殖的成体翼前体细胞凋亡，即使这种稳定的 E2f1 蛋白发生突变，无法诱导转录或细胞周期进程。阻止 S 期稳定的 E2f1 诱导细胞凋亡的能力会导致大量组织过度生长。我们认为，S 期异常的 E2f1 积累会触发细胞凋亡，以消除潜在的过度增殖细胞并维持组织生长期间的稳态。
Precise control of cell cycle regulators is critical for normal development and tissue homeostasis. E2F transcription factors are activated during G1 to drive the G1-S transition and are then inhibited during S phase by a variety of mechanisms. Here, we genetically manipulate the single Drosophila activator E2F (E2f1) to explore the developmental requirement for S phase–coupled E2F down-regulation. Expression of an E2f1 mutant that is not destroyed during S phase drives cell cycle progression and causes apoptosis. Interestingly, this apoptosis is not exclusively the result of inappropriate cell cycle progression, because a stable E2f1 mutant that cannot function as a transcription factor or drive cell cycle progression also triggers apoptosis. This observation suggests that the inappropriate presence of E2f1 protein during S phase can trigger apoptosis by mechanisms that are independent of E2F acting directly at target genes. The ability of S phase-stabilized E2f1 to trigger apoptosis requires an interaction between E2f1 and the Drosophila pRb homolog, Rbf1, and involves induction of the pro-apoptotic gene, hid. Simultaneously blocking E2f1 destruction during S phase and inhibiting the induction of apoptosis results in tissue overgrowth and lethality. We propose that inappropriate accumulation of E2f1 protein during S phase triggers the elimination of potentially hyperplastic cells via apoptosis in order to ensure normal development of rapidly proliferating tissues. Rapidly growing tissues provide an excellent opportunity to study the careful balance between cell proliferation and apoptosis needed for normal organ structure and function in developing organisms. We present evidence that a transcription factor critical for regulating progression of the Drosophila melanogaster cell cycle, E2f1, serves also as an indicator of normal tissue development. E2f1 activation during G1 phase of the cell cycle triggers entry into S phase. E2f1 activity is then rapidly inhibited during S phase by a mechanism that couples E2f1 proteolysis directly to DNA synthesis. Expression during larval development of an S phase-stabilized form of E2f1 results in apoptosis in rapidly proliferating adult wing precursor cells, even when this stabilized E2f1 protein is mutated such that it cannot induce transcription or cell cycle progression. Preventing the ability of S phase-stabilized E2f1 to induce apoptosis results in massive tissue overgrowth. We propose that aberrant E2f1 accumulation during S phase triggers apoptosis in order to remove potentially hyper-proliferative cells and to maintain homeostasis during tissue growth.
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