A message before dying

When a tissue is damaged, cells proliferate just enough to fill in the gap. Jun Huh, Bruce Hay (Caltech, Pasadena, CA), and colleagues now suggest that dying cells produce a signal promoting the multiplication of their surviving neighbors. Figure Death induction causes excess proliferation (white; right, posterior). This type of compensatory proliferation has been recognized for almost 30 years. But the Caltech group stumbled upon the initiating signal while studying downstream mediators of the fly cell death activator Hid. To avoid the “confounding effects” of cell death in these studies they were coexpressing p35, which inhibits downstream caspase enzymes and thus prevents cell death. The result of this fake death regime was enlarged tissues thanks to a 2–4-fold increase in proliferation. “We wondered if it was these undead cells that were sending the [proliferation] signal,” says Hay. Hid kills cells by interfering with the stability and action of DIAP1, a caspase inhibitor. Reduction in DIAP1 levels did not, however, stimulate the compensatory proliferation effect. By contrast, expression of an upstream caspase called Dronc was both necessary and sufficient. The response with Dronc but not low DIAP1 suggests that some of the upstream machinery remains obscure. Another uncertainty is the proliferation-related target of Dronc. Finding protease targets is not easy to do biochemically, so Hay will probably screen for genetic enhancers or suppressors of the compensatory proliferation phenotype. ▪ Reference: Huh, J.R., et al. 2004. Curr. Biol. 10.1016/S0960982204004191.