Lats pathway, proliferation, tissue size in Drosophila

描述(申请人提供)：对细胞增殖和组织大小调节的研究对我们理解发育生物学和肿瘤发生很重要。这项拟议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。我们对花叶果蝇--黑腹果蝇进行了基因筛选，以确定过度生长的突变。已确定的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素，包括LATS肿瘤抑制因子。LATS的突变会导致果蝇显著的过度增殖和肿瘤生长。已经从人类和小鼠中分离出两个哺乳动物LATS同源物Latsi和Lats2，其中至少有一个也具有肿瘤抑制作用。缺乏Latsi的小鼠会患上软组织肉瘤和卵巢肿瘤。生化和遗传学实验表明，LATS家族蛋白是主要的细胞周期调节因子CDKs的负调节因子。然而，LATS激酶的底物尚不清楚。已经在遗传修饰物筛选中发现了几个与LATS相互作用的基因，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，还影响果蝇组织或器官的大小，这一过程尚不清楚。这一建议的具体目的是：(1)确定src64和src42在调节想象组织中的细胞增殖和组织大小中的作用，以及它们与dcsk和lats的关系；(2)确定lats激酶的底物。我们希望，确定LATS相互作用基因之间的关系并确定LATS激酶的底物将为研究发育过程中调节细胞增殖和组织大小的分子机制提供见解。由于LATS和Src的保守哺乳动物同源物已知参与肿瘤的发生，人们进一步希望这些实验也将有助于我们理解人类癌症生物学的潜在机制。

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.