Abstract
Apoptosis is an ancient and evolutionarily conserved cell suicide program. During apoptosis, executioner caspase enzyme activation has been considered a point of no return. However, emerging evidence suggests that some cells can survive caspase activation following exposure to apoptosis-inducing stresses, raising questions as to the physiological significance and underlying molecular mechanisms of this unexpected phenomenon. Here, we show that, following severe tissue injury, Drosophila wing disc cells that survive executioner caspase activation contribute to tissue regeneration. Through RNAi screening, we identify akt1 and a previously uncharacterized Drosophila gene CG8108, which is homologous to the human gene CIZ1, as essential for survival from the executioner caspase activation. We also show that cells expressing activated oncogenes experience apoptotic caspase activation, and that Akt1 and dCIZ1 are required for their survival and overgrowth. Thus, survival following executioner caspase activation is a normal tissue repair mechanism usurped to promote oncogene-driven overgrowth.
Highlights
Apoptosis is an ancient and evolutionarily conserved cell suicide program
We show that executioner caspase activation induced by heat shock, X-ray irradiation, or transient proapoptotic gene overexpression causes extensive cell death in wing imaginal discs, many epithelial cells survive and participate in tissue regeneration
We note that cleaved Dcp-1, which is an active form of the executioner caspase Dcp-1, accumulates detectably only in dead cells
Summary
Apoptosis is an ancient and evolutionarily conserved cell suicide program. During apoptosis, executioner caspase enzyme activation has been considered a point of no return. Survival following executioner caspase activation is a normal tissue repair mechanism usurped to promote oncogene-driven overgrowth. Survival after stress-induced executioner caspase activation has been reported in cardiomyocytes after ischemia-reperfusion[9] and in neurons expressing pathogenic tau[10] in mice. We discovered widespread survival after executioner caspase activation during normal development of Drosophila larval and adult tissues including rapidly proliferating larval imaginal discs[11]. We use the CasExpress sensor to decipher the physiological importance of, and molecular mechanisms enabling, survival from stress-induced executioner caspase activation in vivo. We show that executioner caspase activation induced by heat shock, X-ray irradiation, or transient proapoptotic gene overexpression causes extensive cell death in wing imaginal discs, many epithelial cells survive and participate in tissue regeneration. Survival from executioner caspase activation is a normal cellular response to tissue injury that promotes repair and can be hijacked to drive tumor growth
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