Verschuren, Emma Wilhelmina; (2003) Tumourigenic and tumour suppresive properties of KSHV cyclin in vitro and in vivo. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Expression of the Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) cyclin D homologue, K cyclin, may contribute to viral oncogenesis. This thesis shows that ectopic expression of K cyclin also triggers an apoptotic response. Apoptosis is caspase-dependent and is partially inhibited by expression of either a dominant negative (dn) caspase 9 or the KSHV Bcl-2 homologue, indicating involvement of the mitochondrial apoptotic pathway. Furthermore, even when K cyclin expression does not kill cells directly, it sensitises to induction of apoptosis by various stress signals. In primary fibroblasts, K cyclin expression induces accumulation of transcriptionally active p53 with consequent apoptosis and growth arrest in wild type but not in p53-deficient cells. In contrast, apoptosis is not accompanied by induction of p19ARF protein and requires neither E2F1 nor p19ARF. Interestingly, K cyclin-expressing wt and p53-deficient cells become multinucleated and polyploid. Centrosome analysis of such cells shows that K cyclin expression is associated with centrosome amplification and aneuploidy, which is further exacerbated by p53 loss. I hypothesise that K cyclin expression leads to abortive cytokinesis and polyploidy, ultimately triggering p53-dependent apoptosis and growth arrest. The in vitro data suggest that K cyclin expression is tumourigenic in a p53 null background. To corroborate this, I developed a Eμ K cyclin transgenic mouse model which expresses K cyclin protein in B and T cells. These mice develop lymphomas at a low incidence (10%) and long latency (5-9 months). Tumours often contain mutations in the p53 pathway. Eμ K cyclin mice were crossed with p53 null mice. All K cyclin transgenic p53-/- mice developed B and/or T cell lymphoblastic lymphomas extremely rapidly (around 85 days). These data show that p53 acts as a potent suppressor of K cyclin-induced tumours in vivo.

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