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Title: Investigating the role of RGC-32 in cell cycle disruption by EBV EBNA 3C
Author: Schlick, Sandra
ISNI:       0000 0004 2729 4985
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2010
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Epstein-Barr virus (EBV) immortalises resting B-lymphocyctes and is associated with a diverse range of cancers and establishes a persistent, latent infection in >90% of the world-wide population. Epstein-Barr virus nuclear antigen (EBNA) 3C is one of only six EBV latent proteins that are crucial for B-cell transformation. EBNA3C is known to disrupt cell-cycle control and to progress phase transition at G1/S and G2/M under conditions where cells should growth arrest, but the mechanism by which EBNA3C does this has not been fully determined. The cell-cycle regulator response gene to complement (RGC) 32 was found to be upregulated in EBNA3C-expressing cells in microarray experiments carried out previously. RGC-32 is involved in cell-cycle activation and also plays a role in G1/S and G2/M transition. I have shown that both EBNA3C-expressing cell-lines with upregulated RGC-32 and cell-lines overexpressing RGC-32 alone displayed disrupted G2/M checkpoint control indicating that EBNA3C may overcome cell-cycle control by upregulation of RGC-32. I also confirmed that RGC-32 increases the in vitro kinase activity of CDK1, the key mitotic kinase essential for G2/M transition. Surprisingly, my data showed that EBNA3C only activated RGC- 32 transcription in reporter assays at a very low-level, but stabilised the RGC-32 mRNA. Further studies investigating the differential expression of RGC-32 in EBVpositive and negative cells demonstrated that RGC-32 is upregulated in LCLs and tumour (Burkitt's lymphoma) cell-lines expressing the full panel of latent genes, but intriguingly highly expressed in Burkitt's lymphoma cell-lines expressing only EBNA 1. I found that this expression pattern correlated with expression of the RUNX1 transcription factor. Reporter assays revealed that RUNX1 was able to activate the RGC-32 promoter. Together, this data indicates a new mechanism by which EBNA 3C can disrupt the G2/M checkpoint and highlights a link between RUNX1 and RGC-32 expression in B-cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH0301 Biology ; QR Microbiology