The archipelago tumor suppressor gene limits Rb/E2F-regulated apoptosis in developing Drosophila tissues

• Type of Material: Article
• Authors: Sarah C. Nicholson, Emory University; Melissa Gilbert-Ross, Emory University; Brandon N. Nicolay, University of Illinois; Maxim V. Frolov, University of Illinois; Kenneth H. Moberg, Emory University
• Language: English
• Date: 2009-09-29
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009, Elsevier
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cub.2009.07.068
• Title of Journal or Parent Work: Current Biology
• ISSN: 0960-9822
• Volume: 19
• Issue: 18
• Start Page: 1503
• End Page: 1510
• Grant/Funding Information: KHM was supported by grant GM079242 from the National Institutes of Health.; BNN was supported by NRSA Predoctoral Fellowship 1F31AG032169.; MVF was supported by grant GM079774 from the National Institutes of Health.
• Research Categories: Health Sciences, Oncology; Biology, Genetics; Biology, Cell

Abstract

Background The Drosophila archipelago gene (ago) encodes the specificity component of a ubiquitin-ligase that targets the Cyclin E and dMyc proteins for degradation. Its human ortholog Fbw7 is commonly lost in many cancers, suggesting that failure to degrade ago/Fbw7 targets leads to excess tissue growth. Results Here we show that although loss of ago induces hyperplasia of some organs, it paradoxically shrinks the size of the adult eye. We find that this reflects a requirement for ago to restrict apoptotic activity of the rbf1/e2f1 pathway adjacent to the eye-specific morphogenetic furrow: ago mutant cells display elevated de2f1 activity, express the pro-death dE2f1 targets hid and rpr, and undergo high rates of apoptosis. This death and the resulting small-eye phenotype are dependent on rbf1, de2f1, hid, and the rbf1/de2f1 regulators cyclin E and dacapo, but are independent of dp53. A transactivation-deficient de2f1 allele blocks MF-associated apoptosis of ago mutant cells but does not retard their clonal overgrowth, indicating that intact de2f1 function is required for the death but not overproliferation of ago cells. Alleles of EGFR and wg pathway components further modulate the ago apoptotic and eye size phenotypes, suggesting these pathways control rates of de2f1-driven apoptosis among ago mutant cells. Conclusions These data show that ago loss requires a collaborating block in cell death to efficiently drive tissue overgrowth and that this conditional growth-suppressor phenotype reflects a role for the gene in restricting apoptotic output of the rbf1/de2f1 pathway. Moreover, the susceptibility of ago mutant cells to succumb to this apoptotic program appears to depend on local variations in extracellular signaling that could thus determine tissue-specific fates of ago mutant cells.