TUMOR SUPPRESSORS AND CELL PROLIFERATION IN DROSOPHILA

对细胞增殖调控的研究对我们的 对发育生物学和肿瘤发生的理解。长期的 这项拟议的研究的目标是了解 负向调节细胞增殖。为了解决这个问题， 我们正在识别抑制生长的肿瘤抑制基因，并研究 它们在果蝇发育成象组织中的功能 黑猩猩。该系统的几个方面使其特别适合于 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 (2)一种新开发的基因技术提供了一种 识别影响这种机制的突变的前所未有的机会 在马赛克动物身上，这种机制的组件已经 (3)其他成分可通过未来的遗传鉴定 筛查；以及(4)标准的分子和基因技术可用于 描述这些组件的特征。 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的显著过度增殖 在马赛克动物身上。Lats基因编码一种新的蛋白激酶同源物。 具有一个假定的SH3结合位点。这项建议的具体目标是： (1)继续LATS的分子和基因特征， “93B”和“2-1”基因；以及(2)从基因上鉴定和鉴定 参与细胞增殖负调控的其他基因 或者与LATS相互作用。基因筛查将识别一个网络 在发育过程中参与控制细胞增殖的基因。这个 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 这将有助于在分子水平上理解它们之间的相互作用。 通过这种方式，我们希望了解细胞增殖是如何被调控的 在正常发育期间以及突变如何导致异常生长 和肿瘤的发生。

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.