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，对于理解癌症也至关重要。尽管在这一问题上开展了大量工作，但我们目前只认识到这些机制的一小部分。器官生长控制途径的全面识别将需要作为“系统”级理解的先驱，也将为操纵和临床干预开辟新的途径。果蝇已成为了解基本细胞功能和细胞间相互作用（器官尺寸由其决定）的最佳模型系统。果蝇肿瘤抑制基因（TSGs）的鉴定，即导致细胞和/或器官过度增殖的突变，提供了对已知途径的机制性洞察以及对在脊椎动物中保守的全新器官大小控制途径的鉴定。已经进行了几次对苍蝇TSG的广泛筛选，但这些筛选具有显著的盲点：它们依赖于成体中细胞的存活和适当分化，以及含肿瘤动物的成体存活。我们已经设计并执行了一种新的遗传筛选（“MENE”），其分离了一组以前无法获得的有效的TSGs，其中突变导致低分化的椎间盘细胞（“肿瘤性TSGs”）的致命且通常是无序的过度生长。在这个提议中，我们将使用MENE筛选的新突变体作为切入点，研究两种不同的细胞功能，它们在抑制组织生长方面具有未被重视的作用。第一个涉及由多梳组（PcG）家族的染色质调节因子对生长的表观遗传控制。第二个涉及泛素连接酶，调节细胞增殖和上皮极性。我们将确定这些TSG的生长抑制机制，并将其活动整合到已知的控制椎间盘生长的途径中。最后，我们将扩展肿瘤性TSG的全基因组筛选，以确定抑制椎间盘细胞增殖的其他途径，并阐明所有肿瘤性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并防止肿瘤形成的整个细胞过程。 公共卫生相关性：器官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。果蝇提供了一个简单的模型系统，理想的无偏见的，全基因组识别的基因，防止细胞过度增殖。该提案将阐明两种新的和未被重视的细胞机制如何发挥作用，并与其他已知机制相互作用，以确保苍蝇的适当组织生长，并进一步确定可能在人类中保守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.