The archipelago Tumor Suppressor Gene Limits Rb/E2F-Regulated Apoptosis in Developing Drosophila Tissues

Abstract

Summary 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.

Competition among gene regulatory networks imposes order within the eye-antennal disc of Drosophila

“…The results from these experiments indicate that an epoch of cell death between 72 and 84 hours AEL affects the final size of the eya 2 disc. As Wg signaling has been show to induce cell death in the eye (Cordero et al, 2004;Cordero and Cagan, 2010;Lin et al, 2004;Lim and Tomlinson, 2006;Nicholson et al, 2009), it is a distinct possibility that the induction of wg expression is responsible for the elevated levels of cell death that we see in eya 2 discs. As the eya 2 discs remain smaller throughout the later stages of development, our data also suggests that cell proliferation rates are not elevated to compensate for the earlier apoptosis (see below).…”

Role ofDrosophilaretinoblastoma protein instability element in cell growth and proliferation

“…levels of E2F1 induces pro-apoptotic genes such as p53, Ark/ Apaf1, hid, and reaper. [18][19][20] While hid appears to be responsible for apoptosis in the eye discs, loss of Rbf1 also causes apoptosis in wing imaginal discs. [21][22][23] At the same time, expression of Rbf1 can also induce apoptosis in proliferating cells, an effect that is suppressed by ectopic E2F.…”

mir-11 limits the proapoptotic function of its host gene, dE2f1

“…rpr and hid are direct targets of dE2F1 and miR-11 dE2F1 had been previously shown to activate the expression of hid and rpr and to bind to the hid promoter in asynchronously dividing S2 cells (Asano et al 1996;Moon et al 2008;Nicholson et al 2009). To investigate the role of dE2F1 in the regulation of these genes during DNA damage-induced apoptosis, we examined the occupancy of dE2F1 on the rpr and hid promoters following irradiation.…”