Dying Cells Protect Survivors from Radiation-Induced Cell Death in Drosophila

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.

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

“…It should be pointed out, however, that apoptotic cells have also been shown to induce increased survival of adjacent cells (Bilak et al, 2014). This process depends on activation of the antiapoptosis microRNA Bantam and the receptor tyrosine kinase Tie.…”

“…This process depends on activation of the antiapoptosis microRNA Bantam and the receptor tyrosine kinase Tie. In addition, the Drosophila PDGF/VGF-like protein Pvf1 was identified as a potential signal produced by apoptotic cells and is involved in Tie activation (Bilak et al, 2014). The exact mechanism by which apoptotic signaling modulates cell survival remains to be elucidated.…”

DrosophilaImaginal Discs as a Model of Epithelial Wound Repair and Regeneration

“…Interestingly, ''genuine'' dying cells confer protection on nearby surviving cells, which become harder to kill through a mechanism that involves the micro-RNA bantam. 57 Wound closure. Because the damage that stimulates CP is scattered throughout the tissue, there are no large discontinuities of the epithelium that require closing.…”

“…57 This screen sought mutants in which the living cells failed to carry out enough CP to replace the dying cells. Many mutations isolated affect genes that are also required for normal developmental growth, but CP was particularly sensitive to their loss.…”

The Sound of Silence

“…Additionally, bantam null animals were exceptionally susceptible to ionizing radiation, exhibiting increased apoptosis. However, follow-up studies by the same group revealed the surprising finding that when apoptosis is limited to a specific domain, the increase in bantam , and thus the antiapoptotic effect, was nonautonomous (Bilak, Uyetake, & Su, 2014). These authors found that AiDR, which they termed the “Mahakali” effect, was mediated by the receptor tyrosine kinase Tie on the surviving cell, and the apoptosis-dependent production of the Pvf1 ligand.…”