Effete-mediated degradation of Cyclin A is essential for the maintenance of germline stem cells in Drosophila
Effete-mediated degradation of Cyclin A is essential for the maintenance of germline stem cells in Drosophila
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细胞周期蛋白 A 的 Effete 介导的降解对于维持果蝇生殖干细胞至关重要
DOI：
10.1242/dev.039032
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发表时间：
2009-12-15
期刊：
影响因子：
4.6
通讯作者：
Chen, Dahua
中科院分区：
文献类型：
--
作者：
Chen, Dongsheng;Wang, Qi;Chen, Dahua
越来越多的证据支持干细胞的调节需要外在和内在机制的观点。然而，对内在信号如何调节干细胞的命运知之甚少。对果蝇卵巢生殖干细胞（GSCs）的研究为干细胞维持的调控机制提供了新的见解。在这项研究中，我们证明了由果蝇eff基因介导的泛素依赖性途径，该基因编码E2泛素缀合酶Effete（Eff），在GSC维持中起着至关重要的作用。我们发现，Eff的物理和遗传相互作用与dAPC 2，后期促进复合物（APC），作为一个多亚基E3连接酶的关键组成部分，并在有丝分裂退出过程中降解有丝分裂调节剂的目标发挥着至关重要的作用。这种相互作用表明Eff调节GSC中APC/C介导的蛋白水解途径。此外，我们表明，表达一种稳定形式的细胞周期蛋白A，但不是全长细胞周期蛋白A，导致GSC的损失。最后，我们表明，在共同的APC 2，Eff是必需的泛素化的细胞周期蛋白A，和全长细胞周期蛋白A的过表达加速损失的GSCs在Eff突变的背景。总的来说，我们的数据支持的想法，Effete/APC介导的细胞周期蛋白A的降解是必不可少的维持生殖系干细胞在果蝇。鉴于有丝分裂细胞周期蛋白的调节在果蝇和哺乳动物之间是进化上保守的，我们的研究也意味着类似的机制可能在哺乳动物中是保守的。
Increasing evidence supports the idea that the regulation of stem cells requires both extrinsic and intrinsic mechanisms. However, much less is known about how intrinsic signals regulate the fate of stem cells. Studies on germline stem cells (GSCs) in the Drosophila ovary have provided novel insights into the regulatory mechanisms of stem cell maintenance. In this study, we demonstrate that a ubiquitin-dependent pathway mediated by the Drosophila eff gene, which encodes the E2 ubiquitin-conjugating enzyme Effete (Eff), plays an essential role in GSC maintenance. We show that Eff both physically and genetically interacts with dAPC2, a key component of the anaphase-promoting complex (APC), which acts as a multisubunit E3 ligase and plays an essential role in targeting mitotic regulators for degradation during exit from mitosis. This interaction indicates that Eff regulates the APC/C-mediated proteolysis pathway in GSCs. Moreover, we show that expression of a stable form of Cyclin A, but not full-length Cyclin A, results in GSC loss. Finally we show that, in common with APC2, Eff is required for the ubiquitylation of Cyclin A, and overexpression of full-length Cyclin A accelerates the loss of GSCs in the eff mutant background. Collectively, our data support the idea that Effete/APC-mediated degradation of Cyclin A is essential for the maintenance of germline stem cells in Drosophila. Given that the regulation of mitotic Cyclins is evolutionarily conserved between flies and mammals, our study also implies that a similar mechanism may be conserved in mammals.