Drosophila Tsg101: Coordination of growth control and epithelial polarity

描述(由申请人提供)：我们已经在果蝇的人类肿瘤易感基因101(Tsg101)的同源基因中分离出突变，这是基于它们在发育中的眼睛中的增殖表型。哺乳动物Tsg101在肿瘤发生中的作用仍未解决，其在生长控制中的机制也鲜为人知。完全由Tsg101突变细胞组成的果蝇眼想象盘上皮细胞继续分裂，形成未分化的组织块，表现出上皮极性的缺陷。在果蝇肿瘤抑制基因(NTSGs)之一的突变的想象盘中也观察到了类似的表型。每个nTSG编码一种蛋白质，其定位和调控是建立和维持上皮细胞极性所必需的。因此，Tsg101的调控可能提供了对生长控制和上皮极性之间的联系的洞察，以及最终向肿瘤发生的进展。这项研究计划将直接检验1)Tsg101突变解除调控的主要生长途径和2)Tsg101表型(生长控制和极性缺陷)与nTSGs之间的上位关系。

DESCRIPTION (provided by applicant): We have isolated mutations in the Drosophila ortholog of the human tumor susceptibility gene 101 (Tsg101) based upon their hyperplastic phenotype in the developing eye. A role for mammalian Tsg101 in tumorigenesis remains unresolved and it's mechanism in growth control poorly understood. Drosophila eye imaginal disc epithelia composed entirely of Tsg101 mutant cells continue to divide to form an undifferentiated tissue mass that exhibits defects in epithelial polarity. A similar phenotype is observed in imaginal discs that are mutant for one of the Drosophila neoplastic tumor suppressor class of genes (nTSGs). Each of the nTSGs encodes a protein whose localization and regulation are required for the establishment and maintenance of epithelial cell polarity. Thus, Tsg101 regulation may provide insight into the link between growth control and epithelial polarity, and the ultimate progression towards tumorigenesis. This research proposal will directly test 1) The major growth pathway that is deregulated by Tsg101 mutations and 2) The epistatic relationship between Tsg101 phenotypes (growth control and polarity defects) and the nTSGs.