TUMOR SUPPRESSORS AND CELL PROLIFERATION IN DROSOPHILA

细胞增殖调控的研究对于我们的研究具有重要意义 了解发育生物学和肿瘤发生。长期来看 拟议研究的目标是了解分子机制 负向调节细胞增殖。为了解答这个问题， 我们正在识别生长抑制肿瘤抑制基因并进行研究 它们在果蝇成虫组织发育中的功能 黑腹果蝇。该系统的几个方面使其特别适合 分析负向调节细胞增殖的机制：(1) 已知存在控制细胞增殖的机制 成虫组织； (2) 新开发的遗传技术提供了 识别影响此类机制的突变的前所未有的机会 在嵌合动物中，这种机制的组成部分已经被 已确定； (3) 其他成分可以通过未来的遗传鉴定 屏幕； (4) 标准分子和遗传技术可用于 表征这些组件。 要研究的三个关键基因是lats、“93B”和“2-1”，其中 隐性突变可导致突变细胞急剧过度增殖 在马赛克动物中。 lats 基因编码一种新型蛋白激酶同源物 具有假定的 SH3 结合位点。该提案的具体目标是： (1) 继续进行背阔肌的分子和遗传表征， “93B”和“2-1”基因； (2) 进行遗传鉴定和表征 参与细胞增殖负调控的其他基因 或者与背阔肌相互作用。基因筛选将识别出一个网络 参与发育过程中控制细胞增殖的基因。的 提出的遗传和分子特征将定义 这些基因之间的关系并开始分配生化功能 这将有助于理解它们在分子水平上的相互作用。 通过这种方式，我们希望了解细胞增殖是如何调控的 正常发育期间以及突变如何导致异常生长 和肿瘤发生。

Studies on the regulation of cell proliferation 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 negatively regulate cell proliferation. In order to address this question, we are identifying growth-constraining tumor suppressor genes and studying their functions in the developing imaginal tissues of Drosophila melanogaster. Several aspects of this system make it uniquely suited for analyzing mechanisms that negatively regulate cell proliferation: (1) mechanisms are known to exist in controlling cell proliferation in imaginal tissues; (2) a newly developed genetic technique provides an unprecedented opportunity to identify mutations affecting such mechanisms in mosaic animals, and components of such mechanisms have already been identified; (3) additional components can be identified by future genetic screens; and (4) standard molecular and genetic techniques can be used to characterize these components. The three key genes to be studied are lats, "93B" and "2-1", in which recessive mutations can cause dramatic overproliferation of mutant cells in mosaic animals. The lats gene encodes a novel protein kinase homolog with a putative SH3-binding site. The specific aims of this proposal are: (1) to continue the molecular and genetic characterization of the lats, "93B", and "2-1" genes; and (2) to identify genetically and characterize additional genes involved in the negative regulation of cell proliferation or that interact with lats. The genetic screens will identify a network of genes involved in controlling cell proliferation during development. The genetic and molecular characterizations proposed will define the relationships among these genes and begin to assign biochemical functions which will aid in understanding their interactions at the molecular level. In this manner, we hope to learn how cell proliferation is regulated during normal development and how mutations could lead to abnormal growth and tumorigenesis.