Genetic Models of Apoptosis-Induced Proliferation Decipher Activation of JNK and Identify a Requirement of EGFR Signaling for Tissue Regenerative Responses in Drosophila

Abstract

Recent work in several model organisms has revealed that apoptotic cells are able to stimulate neighboring surviving cells to undergo additional proliferation, a phenomenon termed apoptosis-induced proliferation. This process depends critically on apoptotic caspases such as Dronc, the Caspase-9 ortholog in Drosophila, and may have important implications for tumorigenesis. While it is known that Dronc can induce the activity of Jun N-terminal kinase (JNK) for apoptosis-induced proliferation, the mechanistic details of this activation are largely unknown. It is also controversial if JNK activity occurs in dying or in surviving cells. Signaling molecules of the Wnt and BMP families have been implicated in apoptosis-induced proliferation, but it is unclear if they are the only ones. To address these questions, we have developed an efficient assay for screening and identification of genes that regulate or mediate apoptosis-induced proliferation. We have identified a subset of genes acting upstream of JNK activity including Rho1. We also demonstrate that JNK activation occurs both in apoptotic cells as well as in neighboring surviving cells. In a genetic screen, we identified signaling by the EGFR pathway as important for apoptosis-induced proliferation acting downstream of JNK signaling. These data underscore the importance of genetic screening and promise an improved understanding of the mechanisms of apoptosis-induced proliferation.

During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay

“…This system creates a condition of dying/undead cells flanked by apoptosis-induced cell proliferation of normal cells. Although JNK is activated in apoptotic as well as adjacent surviving cells, it has been shown that the identification of upstream and downstream signaling pathways is much dependent on the apoptosis-inducing system used (47). Hence, the complex tissue heterogeneity created by local cell death seems to obscure a straightforward dissection of the required signaling cascades during normal regeneration.…”

Signaling by the Engulfment Receptor Draper: A Screen in Drosophila melanogaster Implicates Cytoskeletal Regulators, Jun N-Terminal Kinase, and Yorkie

“…It is not known whether yki is activated during engulfment, or what role this might play if so, but both JNK and Yki have been implicated in compensatory proliferation in response to cell death (Ryoo et al 2004;Worley et al 2012). The role of JNK in compensatory proliferation was presumed to occur in the apoptotic cells, perhaps in the generation of proliferative signals from dying cells, but recently activity in the compensating cells has also been demonstrated (Fan et al 2014). This would be consistent with a signal for compensatory proliferation being sent to JNK and Yki when Drpr recognizes apoptotic cells.…”

Rb-mediated apoptosis or proliferation: It's up to JNK

“…AiP in Drosophila channels through the apoptotic machinery, where Dronc/Caspase-9 activates a feedback loop involving JNK and p53. 2,3 However, the underlying mechanisms of AiP lack apparent molecular details. It has been proposed that the molecular mechanisms that distinguish between apoptosis and AiP may rely on specific p53 isoforms (Dp53 or DDNp53 expression, 4 Fig.…”