Cell competition is the process whereby less fit cells termed "losers" are selectively eliminated from a tissue by their fitter neighbors - or " winners." This sacrifice of aberrant cells is thought to have evolved at the advent of multicellularity to enforce cell co-operativity and ensure the fitness of the host organism. Accumulating evidence over the last 40 years has suggested key roles for cell competition during development, adult tissue homeostasis and at the onset and during the progression of diseases including cancer. However, if we are to exploit competition in the treatment of human pathologies and in tissue regeneration, we still have a lot to learn about the underlying mechanisms that ultimately instruct the elimination of loser cells. The main goal of this work was to identify the key molecular events that are responsible for initiating the loser status of Minute heterozygous cells. As many Minute mutations affect ribosomal genes, it has long been assumed that the loser status is closely linked to their associated slow growth phenotype, which occurs a consequence of reduced protein synthesis. Surprisingly, I have found that the loser status is independent of rates of translation. Instead, the activity of a single transcription factor, Nrf2, that typically co-ordinates an oxidative stress response, is sufficient to instruct the elimination of cells by their neighbors. Given the importance of Nrf2, I have sought to identify events occurring both upstream and downstream of the pathway in the loser context. Here, I have shown how multiple loser cell types are suffering from an underlying proteotoxic stress, as a result of an imbalance in proteostasis and their accumulation of toxic protein aggregates. In addition, I have developed a screening strategy to identify key molecules downstream of Nrf2 that could be involved in loser cell recognition. These findings not only provide new insights into the mechanisms of cell competition, but broaden the implications of the process to age-related diseases including those that result in neurodegeneration.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:767756 |
| Date | January 2019 |
| Creators | Dinan, Michael Peter |
| Contributors | Piddini, Eugenia |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/289707 |
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