Abstract
We report a phenomenon wherein induction of cell death by a variety of means in wing imaginal discs of Drosophila larvae resulted in the activation of an anti-apoptotic microRNA, bantam. Cells in the vicinity of dying cells also become harder to kill by ionizing radiation (IR)-induced apoptosis. Both ban activation and increased protection from IR required receptor tyrosine kinase Tie, which we identified in a genetic screen for modifiers of ban. tie mutants were hypersensitive to radiation, and radiation sensitivity of tie mutants was rescued by increased ban gene dosage. We propose that dying cells activate ban in surviving cells through Tie to make the latter cells harder to kill, thereby preserving tissues and ensuring organism survival. The protective effect we report differs from classical radiation bystander effect in which neighbors of irradiated cells become more prone to death. The protective effect also differs from the previously described effect of dying cells that results in proliferation of nearby cells in Drosophila larval discs. If conserved in mammals, a phenomenon in which dying cells make the rest harder to kill by IR could have implications for treatments that involve the sequential use of cytotoxic agents and radiation therapy.
Highlights
In metazoa where cells exist in the context of other cells, the behavior of one affects the others
We showed previously that ban activity increased after exposure to ionizing radiation (IR) in wing imaginal discs of Drosophila larvae [22]
We found that while GFP ban sensor decreased after irradiation in control larvae, reflecting activation of ban (‘wt’ in Fig. 8C, F and I), this decrease was attenuated in tie mutants
Summary
In metazoa where cells exist in the context of other cells, the behavior of one affects the others. Co-expression of caspase inhibitor p35 in dying cells attenuated the protective effect (Table 1) This is in agreement with our data that p35 abolished changes in ban sensor after irradiation [22] and in discs with Hid/Rpr clones (Fig. S2). Wing discs from tie Df(3L)9028 heterozygotes showed an attenuation of both ban activation, as seen by changes in the GFP ban sensor (Fig. S7 and Table 1), and the protective effect of cell death in the ptc domain (Fig. 5L, Table 1). This defect was rescued by one copy of UAS-banA (Fig. 5N and Table 1). The results with Pvf and CG10359 were negative (not shown), but a hemizygote of a Pvf allele, shown before to express no detectable mRNA or protein [33], showed reduced protection (Fig. 5P and Table 1)
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