Mechanisms of Drosophila Tumor Suppression

描述(由申请人提供)：器官在发育和再生过程中控制细胞增殖以达到适当的最终大小的机制是生物学的中心问题，也是理解癌症的关键。尽管在这个问题上进行了密集的工作，但我们目前只对这些机制中的一小部分表示赞赏。对器官生长控制途径的全面识别将是系统层面理解的先导，也将为操作和临床干预开辟新的途径。果蝇已经成为一个最受欢迎的模型系统，用来了解决定器官尺寸的基本细胞功能和细胞间相互作用。果蝇肿瘤抑制基因(TSGs)是导致细胞和/或器官过度增殖的突变，它的发现既提供了对已知途径的机械性洞察，也提供了对脊椎动物中看似保守的全新器官大小控制途径的识别。已经进行了几次广泛的苍蝇TSG筛查，但这些筛查都有一个明显的盲点：它们依赖于成年细胞的存活和适当的分化，以及含肿瘤动物的成年存活。我们设计并执行了一种新的基因筛查(MENE)，该筛查分离出一组以前无法获得的有效TSG，其中的突变会导致低分化的成像盘细胞(肿瘤性TSG)的致命且通常是无序的过度生长。在这项提案中，我们将使用来自Mene筛选的新突变体作为切入点来研究两种不同的细胞功能，它们在抑制组织生长方面的作用尚未得到评价。第一个涉及多梳集团(PcG)染色质调节剂家族对生长的表观遗传控制。第二个涉及泛素连接酶，它同时调节细胞的增殖和上皮的极性。我们将确定这些TSG的生长抑制机制，并将它们的活性整合到已知的控制椎间盘生长的途径中。最后，我们将扩大对肿瘤TSG的全基因组筛查，以确定抑制椎间盘细胞增殖的其他途径，并阐明所有肿瘤TSG活动的共同机制。总之，这些研究将推进我们的长期目标，即了解器官控制其生长和防止肿瘤形成的整个细胞过程星座。 与公共健康相关：器官控制细胞增殖以达到合适的最终大小的机制是生物学的核心问题，也是理解癌症的关键。果蝇提供了一个简单的模型系统，非常适合于无偏见地在全基因组范围内识别防止细胞过度增殖的基因。这项提议将阐明两种新的、未被认识的细胞机制如何发挥作用并与其他已知机制相互作用，以确保果蝇组织的适当生长，并确定更多可能在人类身上保存的新的生长控制机制。

DESCRIPTION (provided by applicant): The mechanisms by which organs control cell proliferation to reach an appropriate final size during development and regeneration are a central question of biology, and are also critical to an understanding of cancer. Despite intensive work on this question, we currently appreciate only a fraction of these mechanisms. Comprehensive identification of organ growth control pathways will be required as a precursor to 'systems'-level understanding, and will also open up new avenues for manipulation and clinical intervention. Drosophila has become a favorite model system for understanding the basic cellular functions and intercellular interactions by which organ dimensions are determined. The identification of Drosophila 'tumor suppressor genes (TSGs)', mutations in which cause cells and/or organs to overproliferate, has provided both mechanistic insight into known pathways as well as the identification of completely new organ size control pathways that appear conserved in vertebrates. Several extensive screens for fly TSGs have been carried out, but these have a significant blind spot: they rely on survival and appropriate differentiation of the cells in the adult, as well as adult survival of the tumor- containing animal. We have designed and executed a novel genetic screen ('MENE') that isolates a previously inaccessible set of potent TSGs, mutations in which cause lethal and often disorganized overgrowth of poorly differentiated imaginal disc cells ('neoplastic TSGs'). In this proposal, we will use new mutants from the MENE screen as an entry point to study two distinct cellular functions with unappreciated roles in restraining tissue growth. The first involves epigenetic control of growth by the Polycomb Group (PcG) family of chromatin regulators. The second involves a ubiquitin ligase that regulates both cell proliferation and epithelial polarity. We will determine the mechanism of growth restraint for these TSGs, and integrate their activities into known pathways controlling disc growth. Finally, we will extend the genome-wide screen for neoplastic TSGs, in order to identify additional pathways that restrain disc cell proliferation and elucidate the common mechanisms that underlie all neoplastic TSG activities. Together, these studies will advance our long-term goal of understanding the entire constellation of cellular processes by which organs control their growth and prevent tumor formation. PUBLIC HEALTH RELEVANCE: The mechanisms by which organs control cell proliferation to reach an appropriate final size are a central question of biology, and are also critical to an understanding of cancer. Drosophila provides a simple model system ideal for unbiased, genome-wide identification of genes that prevent cellular overproliferation. This proposal will elucidate how two new and unappreciated cellular mechanisms function and interact with other known mechanisms to ensure proper tissue growth in the fly, and identify further novel growth-control mechanisms that are likely to be conserved in humans.