Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268394
Title: Analysis of HPV16 E1^E4 induced G2 arrest
Author: Davy, Clare Elizabeth
ISNI:       0000 0001 3418 0992
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Abstract:
Papillomaviruses are small, DNA viruses that infect epithelial tissue and cause hyperproliferative lesions. The majority of human papillomaviruses (HPV) are associated only with benign lesions (warts). However, a small subset of HPVs, e.g. type 16, are associated with lesions that may become malignant, and these viruses are responsible for greater than 99 % of cervical cancers. The expression of the HPV16 E1^E4 protein occurs late during infection and correlates with the onset of vegetative viral DNA replication. Despite being a highly abundant protein that can associate with the cytokeratins, the role of E1^E4 in the virus life cycle is unknown. The work described in this thesis shows that the 16E1^E4 protein can also cause G2 cell cycle arrest. This is apparent both in human cervical epithelial cancer cells and in the fission yeast Schizosaccharomyces pombe. In S.pombe, arrest appears not to be mediated via the "checkpoint" pathways that prevent entry into mitosis by maintenance of the inhibitory phosphorylation on the mitosis promoting factor (MPF) complex. The region of 16E1^E4 responsible for S.pombe arrest lies between amino acids 17 to 45, and arrest is critically dependent on the presence of a threonine residue at position 23. Experiments using recombinant adenoviruses to express 16E1^E4 in human cells show that arrest occurs prior to mitotic chromosome condensation and that a potentially active MPF complex is relocalized to the cytokeratins in 16E1^E4-expressing cells. In human cells, arrest appears to be mediated by inhibition of the nuclear import of cyclin B, a component of the MPF complex. Analysis of mutant 16E1^E4 in human cells suggests that a different mechanism may operate in S.pombe cells. It is suggested that the role of the E1^E4 protein in the virus life cycle is to prevent multiple rounds of cellular replication thereby favouring replication of the viral genome. It is also proposed that the loss of the E4 open reading frame is a predisposing factor for the development of cervical cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.268394  DOI: Not available
Keywords: Human papilloma virus
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