The role of Fas signalling and the c-MYC oncogene in T cell apoptosis and transformation

Morton, Jennifer P (2001) The role of Fas signalling and the c-MYC oncogene in T cell apoptosis and transformation. PhD thesis, University of Glasgow.

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Abstract

Cancer is a disease characterised by disruption of apoptotic pathways and inappropriate expression of survival or proliferative signals. Despite its role as a major apoptotic pathway in T cells however, the role of Fas in lymphomagenesis is not clear. To investigate the role of Fas in MYC induced lymphomagenesis, animals harbouring a c-MYC transgene, with expression targeted to the T cell lineage, were placed on a Faslpr background. Loss of Fas did not alter the incidence, latency or phenotype of thymic lymphomas arising in these mice. In addition, the incidence and latency of lymphomas in Faslpr mice infected with MuLV was not significantly different from strain controlled mice. Further, the proportion of lymphomas with retroviral insertions at c-myc was not increased in Faslpr mice. These results indicate that Fas does not act to restrict tumourigenesis, at least in the T cell lineage. Previous studies have reported that MYC induced apoptosis can occur through Fas and p53 signalling pathways. However loss of Fas did not inhibit MYC induced apoptosis in normal or neoplastic T cells, indicating that MYC induced apoptosis can occur by a Fas independent pathway. Furthermore, MYC induced apoptosis could occur in the combined absence of both Fas and p53 apoptotic pathways. Although loss of these two major apoptotic pathways did not prevent MYC induced apoptosis, protection from MYC induced apoptosis was observed with cell contact in some cell lines. This protection was shown to dependent on a PI3 kinase pathway. In addition, in cell lines that retained functional p53, the PI3 kinase/Akt survival signal was shown to be critical for cell survival. The response to T cell receptor activation in Faslpr thymocytes was also examined. In addition to lacking the ability to undergo activation induced cell death, a proliferative defect was revealed in Faslpr thymocytes, compared with control MRL thymocytes. This defect was rescued by co-stimulation of the cell surface marker CD28. The role of Fas:FasL interactions in tumourigenesis may depend on the cell types in which Fas and FasL are expressed. Signalling through Fas or FasL may be important in the transduction of proliferative signals in T cells, and this may explain why disabling the Fas pathway does not appear to influence T cell lymphomagenesis.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Ewan Cameron
Keywords: Immunology, Cellular biology
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-73169
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 14 Jun 2019 08:56
URI: http://theses.gla.ac.uk/id/eprint/73169

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