Figure 4. Apoptosis induced compensatory proliferation (CP) in various organisms.

In different model organisms apoptosis and caspase activity have been observed to induce secretion of mitogenic factors, thereby promoting hyperplastic overgrowth or tissue regeneration. Mitogenic factors are indicated in pink and question marks indicate uncertainty. A. In Drosophila inhibition of caspases by P35 renders cells in an “undead” state unable to complete apoptosis. This results in the activation of p53 and JNK, triggering the release of the Wg and Dpp mitogens, thereby promoting hyperplasic overgrowth. B. In Drosophila, temporal and spatial apoptosis (in-dependently of p35) induces tissue regeneration via compensatory proliferation by secretion of Wg. A dP53/JNK positive feedback loop is essential for the apoptotic response. C. In Drosophila differentiating neurons induce a different compensatory proliferation pathway, via hedghog (Hh), in a manner requiring both DrICE and Dcp-1. Hh stimulates the proliferation of non-neuronal cells. D. In Hydra, head regeneration post midgut bisection is dependent upon caspase activity, where apoptotic cells secrete Wnt3 promoting CP. E. In newts and planaria, amputation is characterized by apoptosis and caspase activity in the wound site. However it still unknown whether this apoptotic response is responsible for the release of Wnt and Hh. F. In Xenopus, amputation of the tail results in caspase activity, whereas inhibition of caspase-9 and 3 prohibits cell proliferation and the regenerative process. It remains to established whether this form of CP is mediated by Wnt signaling. G. In mice, wound repair and liver regeneration is dependant upon caspase -3 and -7 which are necessary for proper induction of these processes. Caspase-3 mediates the proteolytic processing of iPLA2, which in turn produces archidonic acid the precursor of PGE2, a known stimulator of stem cell proliferation, tissue regeneration and wound repair.