Study of genomic instability caused by HPV16 E6 and E7

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DESCRIPTION (provided by applicant): Genomic instability, resulting in polyploid/ aneuploid cells, is a hallmark of invasive cancers, including those of the head and neck. The presence abnormal numbers of chromosomes in invasive cancer cells is due to loss of cell cycle regulation, resulting in lost of checkpoints and problems at mitosis. Human papillomaviruses (HPV) play a significant role in the etiological of head and neck cancers and we have shown that E6 and E7 from HPV type 16, a virus commonly associated with these cancers, cause polyploidy/ aneuploidy in human epithelial cells. Using microarrays comparing epithelial cells expressing E6 and E7 to control cells, we have found a number of genes involved in the G2 to M phase transition that are deregulated by these viral proteins. The fact that these viral genes cause chromosomal abnormalities suggests that studying their mechanisms of action, may have wider implications for other non-HPV induced cancers. We propose, firstly, to determine what part of mitosis/ cytokinesis is affected in E6/E7-expressing cells. Secondly, investigate the role played by the tumor suppressors, p53 and the retinoblastoma family in the control of G2/M transition. Thirdly, determine how specific G2 and M-phase genes are activated by E6 and E7 and fourthly elucidate, using microarrays, if there are different expression patterns between HPV positive and negative head and neck cancers.