functional interactions between the eruptedtsg101 growth suppressor gene and the dapkc and rbf1 genes in drosophila imaginal disc tumors功能性eruptedtsg101生长抑制基因之间的相互作用和dapkc rbf1基因在果蝇成虫盘肿瘤.pdfVIP

Functional Interactions between the erupted/tsg101 Growth Suppressor Gene and the DaPKC and rbf1 Genes in Drosophila Imaginal Disc Tumors M. Melissa Gilbert, Brian S. Robinson, Kenneth H. Moberg* Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America Abstract Background: The Drosophila gene erupted (ept) encodes the fly homolog of human Tumor Susceptibility Gene-101 (TSG101), which functions as part of the conserved ESCRT-1 complex to facilitate the movement of cargoes through the endolysosomal pathway. Loss of ept or other genes that encode components of the endocytic machinery (e.g. synatxin7/ avalanche, rab5, and vps25) produces disorganized overgrowth of imaginal disc tissue. Excess cell division is postulated to be a primary cause of these ‘neoplastic’ phenotypes, but the autonomous effect of these mutations on cell cycle control has not been examined. Principal Findings: Here we show that disc cells lacking ept function display an altered cell cycle profile indicative of deregulated progression through the G1-to-S phase transition and express reduced levels of the tumor suppressor ortholog and G1/S inhibitor Rbf1. Genetic reductions of the Drosophila aPKC kinase (DaPKC), which has been shown to promote tumor growth in other fly tumor models, prevent both the ept neoplastic phenotype and the reduction in Rbf1 levels that otherwise occurs in clones of ept mutant cells; this effect is coincident with changes in localization of Notch and Crumbs, two proteins whose sorting is altered in ept mutant cells. The effect on Rbf1 can also be blocked by removal of the c- secretase component presenilin, suggesting that cleavage of a c-secretase target influences Rbf1 levels in ept mutant cells. Expression of exogenous rbf1 completel