Department of Cancer Biology
Animals; Apoptosis; Carcinogenesis; Caspases; Cell Proliferation; Drosophila Proteins; Drosophila melanogaster; Humans; MAP Kinase Kinase 4; Models, Genetic; Neoplasms; Receptor, Epidermal Growth Factor; Receptors, Invertebrate Peptide; Regeneration; Wnt Signaling Pathway; rho GTP-Binding Proteins
Cancer Biology | Cell Biology | Genetics | Molecular Genetics
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.
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© 2014 Fan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS Genet. 2014 Jan 30;10(1):e1004131. doi: 10.1371/journal.pgen.1004131. eCollection 2014. Link to article on publisher's site
Fan, Yun; Wang, Shiuan; Hernandez, Jacob; Yenigun, Vildan Betul; Hertlein, Gillian; Fogarty, Caitlin E.; Lindblad, Jillian L.; and Bergmann, Andreas, "Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila" (2014). University of Massachusetts Medical School Faculty Publications. 420.
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