Understanding the cellular pathways regulated by Dis3L2 in cell proliferation.

细胞增殖的调控对所有多细胞生物都至关重要。细胞必须在整个发育过程中增殖，以使生物体从卵子长成成人。在伤口愈合过程中，增殖也必须发生以修复受损区域。控制增殖对于使单个动物及其组成器官的生长达到且不超过其正确大小，以及保持动物左右两侧的对称至关重要。不受控制的细胞增殖是癌症的一个标志，许多基因参与了与癌症进展有关的生长和增殖。用果蝇作为模型生物，我们最近发现细胞增殖可以被一种叫做Dis3L2的酶调节。众所周知，这种酶会破坏信使RNA分子（mrna），而信使RNA分子会指示细胞制造特定的蛋白质。通过比较缺乏Dis3L2的突变果蝇和正常个体，我们发现缺乏Dis3L2的果蝇翅膀比正常果蝇大得多。突变体的翅膀从幼虫的翅膀想象圆盘中生长出来，翅膀也要大得多。我们的研究结果特别有趣，因为类似的人类基因DIS3L2的突变会导致帕尔曼综合征和一种叫做威尔姆斯瘤的肾癌的易感性。帕尔曼综合征是一种生长过度的疾病，受影响的儿童表现出产前巨人症和器官（如肾脏）的异常扩大。因此，果蝇和人类的Dis3L2突变都会导致某些器官内的细胞过度生长，这表明了这些生物体之间这种生物学途径的良好保存，并证明了果蝇对了解这种疾病的有用性。使用最先进的分子方法，我们发现缺乏Dis3L2会导致一些特定mrna水平的增加。其中一些mrna的已知功能为理解Dis3L2在果蝇和人类中的功能提供了分子途径。我们的假设是，Dis3L2通常通过限制细胞内的能量产生以及调节重要细胞资源的水平来控制增殖。由于增殖细胞需要更多的能量来促进它们的快速生长，这个假设与我们在果蝇中看到的组织过度生长是一致的。我们有专业知识，也有分子和基因工具来检验这个假设。拟议中的项目是完全新颖的；到目前为止，还没有研究小组阐明了Dis3L2在发育生物体的自然环境中控制增殖的机制。以前的研究使用的是单个组织培养细胞或永生化细胞，而不是自然组织中的正常细胞，因此错过了有关细胞途径的线索。由于控制果蝇生长的细胞途径与人类非常相似，在这个项目中获得的知识可能有助于我们了解正常组织生长和发育的方式。这一知识也将有助于找到促进组织再生的方法，例如在肝脏再生过程中发生的组织再生。它在寻找对抗癌症期间发生的不受控制的增殖的治疗方法方面也很重要。如果我们的实验证实Dis3L2通过代谢途径控制增殖，这将提供一种强大的对抗癌症的方法，因为癌细胞很难绕过它们对高代谢率的需求。因此，该项目将为新的细胞途径提供有价值的见解，可用于开发新的疾病治疗方法。

Regulation of cell proliferation is of crucial importance to all multicellular organisms. Cells must proliferate throughout development in order for the organism to grow from an egg to an adult. Proliferation must also occur to repair damaged areas during the process of wound healing. Control of proliferation is vitally important to allow individual animals and their constituent organs to grow to reach and not exceed their correct sizes, as well as to maintain symmetry between the left and right sides of an animal. Uncontrolled cell proliferation is a hallmark of cancer with many genes involved in growth and proliferation implicated in cancer progression. Using fruit flies as a model organism, we have recently discovered that cell proliferation can be regulated by an enzyme named Dis3L2. This enzyme is known to destroy messenger RNA molecules (mRNAs) which instruct the cell to make particular proteins. By comparing mutant fruit flies lacking Dis3L2 with normal individuals, we have found that lack of Dis3L2 results in wings that are much larger than normal. The wings grow from larval wing imaginal discs, which are also much larger in the mutant. Our results are particularly interesting because mutations in the equivalent human gene, DIS3L2, result in Perlman syndrome and susceptibility to a kidney cancer called Wilms' tumour. Perlman syndrome is an overgrowth condition where affected children display pre-natal gigantism and abnormal enlargement of organs (e.g. kidneys). Therefore mutations in Dis3L2 in both fruit flies and humans result in the overgrowth of cells within some organs, showing an excellent conservation of this biological pathway between these organisms and demonstrating the usefulness of fruit flies to understand this disease.Using state-of-the-art molecular methods, we have discovered that a lack of Dis3L2 results in an increase in levels of a few specific mRNAs. The known function of some of these mRNAs suggest a molecular pathway for understanding the function of Dis3L2 in flies and humans. Our hypothesis is that Dis3L2 normally controls proliferation by limiting energy production within the cell as well as regulating the levels of important cellular resources. Since proliferating cells require more energy to fuel their rapid growth, this hypothesis is consistent with the tissue overgrowth we see in our fruit flies. We have the expertise, as well as the molecular and genetic tools to test this hypothesis. The proposed project is entirely novel; as yet no research group has elucidated the mechanisms whereby Dis3L2 controls proliferation in the natural context of a developing organism. Previous studies have used individual tissue culture cells or immortalised cells in culture rather than normal cells in a natural tissue therefore have missed clues about the cellular pathways involved. Since the cellular pathways controlling growth in fruit flies are very similar to those in humans, the knowledge gained during this project may help us to to understand the ways that normal tissues grow and develop. This knowledge will also be useful in finding ways to promote controlled regeneration of tissues such as that which occurs during liver regeneration. It will also be important in the search for therapies to combat uncontrolled proliferation, as occurs during cancer. Should our experiments confirm that Dis3L2 controls proliferation via metabolic pathways, this will provide a powerful way of combatting cancer as it will be difficult for cancer cells to circumvent their need for high metabolic rates. This project will therefore provide valuable insights into a new cellular pathway which can be used in the development of new disease therapeutics.