Drosophila Tsg101: Coordination of growth control and epithelial polarity

描述（由申请人提供）：我们根据人肿瘤易感基因101（Tsg101）在发育中眼睛中的增生表型，分离出果蝇直系同源基因中的突变。哺乳动物Tsg101在肿瘤发生中的作用尚未得到解决，其生长控制机制也知之甚少。果蝇眼的成虫盘上皮完全由Tsg101突变细胞组成，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）突变的成虫盘中观察到类似的表型。每个nTSG编码一种蛋白质，其定位和调节是建立和维持上皮细胞极性所必需的。因此，Tsg101调节可能提供洞察生长控制和上皮极性之间的联系，并最终进展到肿瘤发生。本研究提案将直接测试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.