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Abstract
BackgroundTumor Susceptibility Gene-101 (TSG101) promotes the endocytic degradation of transmembrane proteins and is implicated as a mutational target in cancer, yet the effect of TSG101 loss on cell proliferation in vertebrates is uncertain. By contrast, Drosophila epithelial tissues lacking the TSG101 ortholog erupted (ept) develop as enlarged undifferentiated tumors, indicating that the gene can have anti-growth properties in a simple metazoan. A full understanding of pathways deregulated by loss of Drosophila ept will aid in understanding potential links between mammalian TSG101 and growth control.Principal FindingsWe have taken a genetic approach to the identification of pathways required for excess growth of Drosophila eye-antennal imaginal discs lacking ept. We find that this phenotype is very sensitive to the genetic dose of stat92E, the transcriptional effector of the Jak-Stat signaling pathway, and that this pathway undergoes strong activation in ept mutant cells. Genetic evidence indicates that stat92E contributes to cell cycle deregulation and excess cell size phenotypes that are observed among ept mutant cells. In addition, autonomous Stat92E hyper-activation is associated with altered tissue architecture in ept tumors and an effect on expression of the apical polarity determinant crumbs.ConclusionsThese findings identify ept as a cell-autonomous inhibitor of the Jak-Stat pathway and suggest that excess Jak-Stat signaling makes a significant contribution to proliferative and tissue architectural phenotypes that occur in ept mutant tissues.
Highlights
These findings identify ept as a cell-autonomous inhibitor of the Jak-Stat pathway and suggest that excess JakStat signaling makes a significant contribution to proliferative and tissue architectural phenotypes that occur in ept mutant tissues
The Drosophila gene erupted encodes an ortholog of human Tumor Susceptibility Gene-101 (TSG101) and yeast Vps23p, which function as part of the ESCRT-I complex to sort proteins to the multivesicular body for ultimate lysosomal degradation [1,2,3]
Mutations in the ept/tsg101 gene or the ESCRT-II subunit gene vps25 block endocytic degradation of certain transmembrane proteins and lead to dramatic overgrowth of imaginal discs [4,5,6,7], a set of polarized epithelial tissues that grow during larval stages and go on to form the majority of adult structures
Summary
The Drosophila gene erupted (ept) encodes an ortholog of human Tumor Susceptibility Gene-101 (TSG101) and yeast Vps23p, which function as part of the ESCRT (endosomal sorting complex required for transport)-I complex to sort proteins to the multivesicular body for ultimate lysosomal degradation [1,2,3]. Mutations in the ept/tsg101 gene (referred to hereafter as ept) or the ESCRT-II subunit gene vps block endocytic degradation of certain transmembrane proteins and lead to dramatic overgrowth of imaginal discs [4,5,6,7], a set of polarized epithelial tissues that grow during larval stages and go on to form the majority of adult structures. This imaginal disc overgrowth occurs in part by a noncell autonomous process: ept and vps mutant cells themselves undergo very high rates of apoptosis, but can potently induce growth of surrounding genetically normal tissue due to overproduction of secreted factors like Unpaired (Upd) [4,5,6], a secreted cytokine-like mitogen that activates Jak-STAT signaling via the receptor Domeless (Dome) [8]. A full understanding of pathways deregulated by loss of Drosophila ept will aid in understanding potential links between mammalian TSG101 and growth control
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