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达到适当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。尽管在这个问题上进行了大量工作，但我们目前只了解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，也将为操作和临床干预开辟新的途径。果蝇已经成为理解基本细胞功能和细胞间相互作用的一个最受欢迎的模型系统，器官的大小是由这些相互作用决定的。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洞察，以及对脊椎动物中似乎保守的全新器官大小控制途径的鉴定。已经对蝇类tsg进行了几次广泛的筛选，但这些筛查存在一个明显的盲点：它们依赖于成虫体内细胞的存活和适当分化，以及含瘤动物的成虫存活。我们设计并实施了一种新的遗传筛选方法（MENE），该方法分离出一组以前无法获得的强效tsg，这些突变会导致低分化的影像学椎间盘细胞（“肿瘤性tsg”）致命且经常无序的过度生长。在本提案中，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，这些功能在抑制组织生长方面具有未被认识的作用。第一个涉及染色质调节因子Polycomb Group （PcG）家族对生长的表观遗传控制。第二种涉及调节细胞增殖和上皮极性的泛素连接酶。我们将确定这些tsg的生长抑制机制，并将其活性整合到控制椎间盘生长的已知途径中。最后，我们将扩大肿瘤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TSG活性的共同机制。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。

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.