Kiso, Koshiro;
(2025)
An investigation into the contribution of c-Myc induced changes to nuclear architecture towards early stage
oncogenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Abnormal nuclear morphologies (nuclear atypia) are a common and widespread feature of cancer cells and are robust enough to be used as diagnostic markers for tumour tissue. However, the mechanisms leading to the generation of these morphologies, as well as their potential contribution towards the tumourigenic and tumour evolution process are two aspects that have not received much study until recently. In this project, I focus on the contribution of oncogene induced alterations to nuclear morphology and architecture towards early stage oncogenesis. Using an oncogene inducible cell line as a model system, I show that c-Myc activity causes acute and significant changes to nuclear morphology and that it leads to both a reduction and a mislocalisation of components of the nuclear lamina (lamins A and B1). Following on from this, I provide evidence suggesting that this c-Myc induced downregulation of lamin A in particular is partially mediated by its induction of the micro-RNA molecule miR-9. I also show that c-Myc induced nuclear morphology defects and lamin A mislocalisations are partially cell cycle and mitosis dependent. Finally, I show that c-Myc induction causes nuclei to undergo an increased frequency of nuclear envelope rupture (NER) events, that could then contribute towards oncogenesis by leading to increasing levels of DNA damage and genomic instability (GIN). Taken together, my work highlights a novel potential pathway of oncogenesis which involves the direct dysregulation of components maintaining nuclear morphology in untreated cells that then leads to increases in downstream genome instability. This work has interesting implications for the understanding of cancer cell evolution as it suggests that dysregulation of nuclear morphology is a phenomenon that occurs very early in the oncogenic process and that it is an important driver of subsequent tumour cell evolution.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | An investigation into the contribution of c-Myc induced changes to nuclear architecture towards early stage oncogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10211282 |
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