The role of p53 in virus-induced and multi-step lymphomagenesis

It has previously been demonstrated that p53 loss and Moloney murine leukaemia virus (MMLV) infection are weakly collaborative in T cell lymphomagenesis. The work described in this thesis aimed to investigate the role of p53 in MMLV-induced lymphoma and explore the basis of their relatively weak collaboration. The effects of p53 loss in combination with MMLV were explored first in primary fibroblasts. While no viral cytopathology was observed in these cells, it was found that the virus conferred a growth advantage on infected cells that was additive with the effects of p53 loss. MMLV has been reported to induce a preleukaemic phase of apoptosis in the thymus of infected mice and the role of p53 in this phenomenon was investigated next. The response was found to be short-lived, with peak onset varying according to host mouse strain. No evidence of direct induction of p53 was observed in thymus tissue in vivo, but evidence on the p53 dependence of the MMLV-induced apoptosis was equivocal, yielding only provisional conclusions. The role of p53 was then examined at the later stages of MMLV disease and tumours were analysed for loss of heterozygosity of the wild type p53 allele and expression of functional p53 protein with prolonged in vitro and in vivo passage. Two mouse models were used; a cohort of MMLV-infected mice and also a Runx2/Myc surrogate model which develop tumours after a significantly reduced latent period. The data suggested that whilst p53 loss is obligatory for in vitro culture of tumour cells, it is not required for the growth of tumours passaged in vivo. The sparing effect was not absolute, however, and there was some evidence of p53 pathway inactivation and allele loss in progressing tumours. In summary, I conclude that the weak synergy observed between MMLV and p53 loss is principally due to functional overlap, largely driven by activation of MMLV target genes such as Myc and Runx2 that collaborate to suppress p53-dependent pathways in vivo.

Level dc:type.qualificationlevel

PhD

Grantor dc:publisher.institution

University of Glasgow

Year dc:date.issued

2009

Author dc:creator

• Long, Fenella H.A.

• RC0254 Neoplasms. Tumors. Oncology (including Cancer)

Language dc:language

en