Lats pathway, proliferation, tissue size in Drosophila

描述（由申请人提供）：关于细胞增殖和组织大小调节的研究对于我们理解发育生物学和肿瘤发生非常重要。这项研究的长期目标是了解在发育过程中调节细胞增殖和组织大小的分子机制。我们已经在花叶果蝇中进行了遗传筛选，以确定过度生长突变。已鉴定基因的分子和遗传特征揭示了细胞增殖、细胞生长和组织大小的几个关键调节因子，包括lats肿瘤抑制因子。在果蝇中，lats的突变导致显著的过度增殖和肿瘤生长。两种哺乳动物lats同源物，Latsi和Lats 2，已经从人类和小鼠中分离出来，并且其中至少一种也具有肿瘤抑制剂的功能。缺乏Latsi的小鼠会发展成软组织肉瘤和卵巢肿瘤。生物化学和遗传学实验表明，Lats家族蛋白是主要细胞周期调节因子CDK的负调节因子。然而，Lats激酶的底物是未知的。在遗传修饰剂筛选中已经鉴定了几个lats相互作用基因，包括Src家族成员。有趣的是，lats及其相互作用的基因不仅影响细胞增殖，而且在果蝇中解除组织或器官大小的调节，这一过程尚未得到很好的理解。本提案的具体目标是：（1）表征Src 64和Src 42在调节细胞增殖和组织大小中的作用，以及它们与dcsk和lats的关系;和（2）鉴定Lats激酶的底物。我们希望，定义之间的相互作用的Lats基因的关系，并确定底物的Lats激酶将提供深入了解在发展过程中调节细胞增殖和组织大小的分子机制。由于已知Lats和Src的保守哺乳动物同源物参与肿瘤发生，因此进一步希望这些实验也有助于我们理解人类癌症生物学的机制。

DESCRIPTION (provided by applicant): Studies on the regulation of cell proliferation and tissue size are important to our understanding of developmental biology and tumorigenesis. The long-term goal of the proposed research is to learn the molecular mechanisms that regulate cell proliferation and tissue size during development. We have performed genetic screens in mosaic fruit flies, Drosophila melanogaster, to identify overgrowth mutations. Molecular and genetic characterization of the identified genes have revealed several key regulators of cell proliferation, cell growth, and tissue size, including the lats tumor suppressor. Mutations in lats cause dramatic overproliferation and tumor growth in Drosophila. Two mammalian lats homologs, Latsi and Lats2, have been isolated from humans and mice, and at least one of them also functions as a tumor suppressor. Mice deficient for Latsi develop soft tissue sarcomas and ovarian tumors. Biochemical and genetic experiments have shown that the Lats family proteins are negative regulators of the major cell cycle regulators, CDKs. However, substrates for the Lats kinase are unknown. Several lats-interacting genes have been identified in genetic modifier screens, including Src family members. Interestingly, lats and its interacting genes not only affect cell proliferation, but also deregulate tissue or organ size in Drosophila, a process which is not well understood. The specific aims of this proposal are: (1) Characterizing the roles of Src64 and Src42 in the regulation of cell proliferation and tissue size in imaginal tissues and their relationships with dcsk and lats; and (2) Identifying substrates for the Lats kinase. We hope that defining the relationships among the lats-interacting genes and identifying substrates of the Lats kinase will provide insights into molecular mechanisms regulating cell proliferation and tissue size during development. Since conserved mammalian homologs of Lats and Src are known to be involved in tumorigenesis, it is further hoped that these experiments will also contribute to our understanding of mechanisms underlying human cancer biology.