Rb and Hippo tumor suppressor pathways in differentiation

项目总结/摘要 在多细胞生物体中，细胞增殖和分化的控制由细胞的净输出决定。 多重途径这是由著名的Rb肿瘤抑制基因 途径和新兴的Hippo肿瘤抑制途径。然而，这些类型的研究 本质上是复杂的，因此模式生物如果蝇是有吸引力的替代品， 补充哺乳动物系统中的类似研究。这主要是由于相对简单， 果蝇Rb和Hippo通路的高度保守性。在上一个赠款周期，我们 探讨了海马和Rb通路在调节 细胞增殖，并确定了这些途径的新作用。我们发现了Rb的一个新功能 途径的调控，并表明，损失的表达， 这种调节导致果蝇和人类肿瘤细胞中严重的线粒体缺陷。我们也 表明Rb通路在果蝇成年骨骼肌中具有重要功能， 这是动物生存所必需的和足够的。我们的建议建立在这些观察的基础上， Rb和Hippo通路的这些新方面超出了它们在细胞增殖中的传统作用。在 特别是，我们将确定这两种途径如何合作，以调节果蝇线粒体功能 并将利用这些知识来指导我们提高CDK 4/6抑制剂的治疗效果， 肿瘤细胞此外，我们将探讨Rb通路在成人骨骼肌中的重要性， 定义潜在的机制。最后，我们将使用一种新的遗传细胞标记系统，单细胞 方法和先进的基因组工具来阐明海马和 Rb通路在体内维持终末分化。总的来说，这些研究将提高我们的 肿瘤抑制途径的合作知识，并将有助于确定新的 治疗目标

PROJECT SUMMARY/ABSTRACT In a multicellular organism, control of cell proliferation and differentiation is determined by the net output of multiple pathways. This is illustrated by cooperation between the well-known Rb tumor suppressor pathway and the emerging Hippo tumor suppressor pathway. However, these types of studies are intrinsically complex and therefore model organisms such as Drosophila are attractive alternatives to complement analogous studies in mammalian systems. This is due primarily to the relative simplicity yet high conservation of the Drosophila Rb and Hippo pathways. In the previous cycle of this grant, we explored the mechanistic details of cooperation between the Hippo and Rb pathways in the regulation of cell proliferation and identified new roles of these pathways. We discovered a novel function of the Rb pathway in the regulation of expression of mitochondria-associated genes and showed that the loss of such regulation results in severe mitochondrial defects, both in flies and in human tumor cells. We also showed that the Rb pathway has an essential function in Drosophila adult skeletal muscles that is necessary and sufficient for animal viability. Our proposal builds on these observations to investigate these new aspects of the Rb and Hippo pathways beyond their conventional role in cell proliferation. In particular, we will determine how the two pathways cooperate to regulate the mitochondrial function in flies and will use this knowledge to guide us towards improving the therapeutic effects of a CDK4/6 inhibitor in tumor cells. Additionally, we will explore the importance of the Rb pathway in adult skeletal muscles and define the underlying mechanisms. Finally, we will use a novel genetic cell-labeling system, single-cell approaches and advanced genomic tools to elucidate the molecular mechanisms by which the Hippo and Rb pathways maintain terminal differentiation in vivo. Collectively, these studies will enhance our knowledge of the cooperation of tumor suppressor pathways and will contribute to the identification of new therapeutic targets.