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Periodic Report Summary 1 - MECHAIP (Deciphering the molecular mechanisms of apoptosis-induced cell proliferation)

In multi-cellular organisms, stress-induced apoptotic cells are able to stimulate their neighbouring cells to undergo compensatory proliferation, a process termed apoptosis-induced proliferation (AiP). Studies in several model organisms including mammals have suggested that AiP is evolutionarily conserved and relevant to both tissue regeneration and tumourigenesis. Intriguingly, caspases, the proteases that normally execute apoptosis, have been implicated to play key roles in AiP through activation of their downstream growth signals. However, the underlying mechanism of AiP remains elusive. Systematic approaches are thus in need to dissect the regulatory network of AiP. By taking advantages of the developing Drosophila eye as an epithelium composed of both proliferating and differentiating tissues, our previous work has revealed that distinct mechanisms of AiP exist in tissues with different developmental potentials. In the proliferating tissue where cells are actively dividing, the initiator caspase (Caspase-9 like) coordinates apoptosis and AiP; while in the differentiating tissue where cells have exited the cell cycle, the effector caspases (Caspase-3 like) activate cell cycle re-entry. Built upon this finding, the goal of the MechAiP project is to obtain a comprehensive understanding of AiP. To achieve this, we have developed sensitive and unique assays for analysis of AiP in Drosophila epithelial tissues. By employing these assays together with proteomic approaches and systematic screens, we aim at (1) determining how caspases initiate AiP in apoptotic cells; (2) elucidating how AiP-mediating growth signals including the Wg/Wnt, Dpp/ TGF-β and Spitz/EGF signalling pathways are activated downstream of caspases; and (3) identifying and characterizing critical kinase regulators of AiP in both proliferating and differentiating tissues.

With support of the CIG MechAiP grant, the following work has been performed during this reporting period: (1) Conducting a kinome-wide RNAi screen and developing biochemical assays to identify regulators of AiP in the proliferating eye tissue; (2) Validating and characterizing roles of identified potential AiP regulators in the proliferating tissue; (3) Further characterizing cellular apoptotic responses in the differentiating eye tissue which is relevant to understanding of AiP in the differentiating tissue; (4) Further developing and characterizing assays that can facilitate analysis of AiP and its regulators in the differentiating tissue.

By doing these, we have successfully completed the kinome-wide RNAi screen in the proliferating tissue. The screen itself and identification of a set of kinases in the c-Jun kinase (JNK) signalling pathway have been published in the journal PLoS Genetics (doi: 10.1371/journal.pgen.1004131). Other potential AiP regulators identified are currently under further investigating. In addition, the work to characterize cellular apoptotic responses in the differentiating eye tissue has identified distinct molecular mechanisms that can modulate cellular susceptibility to apoptosis. This finding has been published in the journal Developmental Cell (doi: 10.1016/j.devcel.2014.05.007). Following this study, we are further developing and testing new AiP screen assays in the differentiating tissue with the aim to identify novel AiP regulators in this cellular context.

In summary, through gradual build-up of our knowledge on AiP in both proliferating and differentiating tissues, by the end of the project, we expect to achieve a comprehensive understanding of AiP with identification of key regulators of such a cellular communication process. Further characterizing how the identified key regulators control AiP will close gaps in our knowledge and may provide potential drug targets for regenerative medicine and cancer therapy.

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United Kingdom


Life Sciences