Regulation of apoptosis and compensatory proliferation by DIAP1

H. Ryoo, T. Gorenc, H. Steller. HHMI, Rockefeller Univ, New York, NY.

Cell proliferation and death is tightly linked during animal development. In Drosophila, cells doomed to die activate the expression of reaper, hid and grim, which bind and inhibit the essential anti-apoptotic protein, DIAP1. In imaginal discs, dying cells are compensated by extra-proliferation, thereby maintaing proper size during development. To test if this compensatory proliferation is due to an active signaling activity from dying cells, we generated diap1 -/- clones and rescued their lethality by expressing the caspase inhibitor p35. Under these conditions, overcompensation was observed where the surviving diap1 -/- cells induced massive BrdU incorporation around them, thereby increasing the size of imaginal discs. Similarly, inhibiting DIAP1 through co-expression of hid and p35 led to overcompensation, indicating that a signaling activity may persist by keeping these cells alive. The effect on proliferation was dependent on the DIAP1 ubiquitin-ligase motif, as clones of diap1 alleles specifically disrupting the RING domain also induced BrdU labeling. One ubiquitylation target of DIAP1 is TRAF1 and the Jun-kinase pathway. To test the role of the Jun-kinase pathway in compensatory proliferation, we sensitized this pathway by reducing puckered dosage, a negative regulator of Jun-kinase. Whereas expressing reaper and p35 had minimal effect in BrdU incorporation, reaper and p35 expression in puckered -/+ enhanced BrdU incorporation non-autonomously. Our results support the model where cells undergoing apoptosis inhibit DIAP1, thereby activating the Jun-kinase pathway. This may induce mitogen expression that signal to neighboring cells for compensatory proliferation.

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