Phinichkusolchit, Narisa (2021) ROCK1-mediated apoptotic blebbing in genetic models of tissue homeostasis and tumourigenesis. PhD thesis, University of Glasgow.
Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.Abstract
Apoptosis is a controlled form of cell death that contributes to the removal of unwanted cells to maintain tissue homeostasis. Cells undergoing apoptosis display characteristic morphological changes including apoptotic membrane blebbing and apoptotic body formation. The Rho associated coiled-coiled containing kinase (ROCK) 1 is cleaved upon the activation of caspase-3 during apoptosis, resulting in a hyper-activated truncated form of the protein. This drives actin-myosin contractions to form dynamic apoptotic membrane blebs. In order to dissect the specific functionality of ROCK1-mediated apoptotic membrane blebbing, the Olson lab generated a mouse model of a mutant, noncleavable form of ROCK1 (ROCK1nc). This unique model has been studied under conditions of tissue homeostasis focusing on thymic development and apoptotic cell clearance within the thymus.
The ROCK1nc mutation did not affect the anatomical and cellular properties of the thymus under physiological conditions, nor when challenged with apoptosis inducing agent dexamethasone. However adoptive transfer experiments did reveal that injection of apoptotic thymocytes into ROCK1nc recipients yielded greater immune cell infiltration in comparison to ROCK1wt recipients. As no differences were observed between the genotypes during apoptotic conditions. These results suggest that apoptotic membrane blebbing is likely dispensable in maintaining homeostasis in the thymus.
The importance of apoptotic membrane blebbing was also investigated in agenetic mouse model of lung adenocarcinoma. Here the addition of the ROCK1nc mutation accelerated tumourigenesis with animals succumbing to lung tumours at a significantly earlier time. Interestingly while this particular model of lung adenocarcinoma is characterised by increased immunogenicity, the acceleration with ROCK1nc was not attributed to immune cell infiltration. These results suggest that defective apoptotic membrane blebbing is important in facilitating tumourigenesis in lung adenocarcinomas. Taken together, the results shown here indicate that apoptotic morphology alters tumourigenesis to a greater extent than homeostasis itself. These studies allow for a better understanding of the functions of apoptotic membrane blebbing and shed light on whether ROCK inhibitors could be used for the treatment of different cancers.
| Item Type: | Thesis (PhD) |
|---|---|
| Qualification Level: | Doctoral |
| Keywords: | ROCK1, Rho-associated coiled coiled containing kinase, Apoptosis, Blebbing, Thymus, Lung Adenocarcinoma, p53, MDM2. |
| Subjects: | Q Science > QH Natural history > QH301 Biology |
| Colleges/Schools: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research |
| Supervisor's Name: | Blyth, Professor Karen and Olson, Professor Michael |
| Date of Award: | 2021 |
| Embargo Date: | 9 January 2024 |
| Depositing User: | Miss Narisa Phinichkusolchit |
| Unique ID: | glathesis:2021-81903 |
| Copyright: | Copyright of this thesis is held by the author. |
| Date Deposited: | 11 Jan 2021 08:09 |
| Last Modified: | 01 Jun 2021 17:10 |
| Thesis DOI: | 10.5525/gla.thesis.81903 |
| URI: | https://theses.gla.ac.uk/id/eprint/81903 |
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