Regulation of HPV 16-E7 by E2, Phosphorylation and the Proteasome

Gammoh, Noor (2007). Regulation of HPV 16-E7 by E2, Phosphorylation and the Proteasome. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fd51

Abstract

In order to ensure a productive life cycle, Human Papillomaviruses (HPVs) require fine regulation of their gene products. Uncontrolled activity of the viral oncoproteins, E6 and E7, results in the immortalisation of the infected epithelial cells and thus prevents the production of mature virions. Here, we investigate the regulation of HPV-16 E7 activities through its interaction with both viral and cellular gene products. First, we show that HPV-16 E7 and E2 can interact directly and the region mediating this interaction is defined on each protein. The expression of E2 inhibits some of E7 oncogenic activities including primary cell transformation, induction of centrosome abnormalities and pRB degradation. In addition, E2 can stabilise E7 and redirect its localisation where it can associate with some of E2’s activities such as transcriptional activation and mitotic chromosome binding. Secondly, we provide evidence that E7 can be phosphorylated by CDK2 in vitro preferentially on its N-terminal domain, and we hypothesise that this occurs on more than one residue on E7. In vivo, we show that the activity of CDK2, as well as CKII, is necessary for the stability of E7. Finally, we identified an interaction between HPV-16 E2 and E7 with the cellular oncoprotein, Mdm2. Mdm2 appears to destabilise E7 targeting it to proteasome-mediated degradation at PML bodies. The stability of E7 in cells that have reduced expression of Mdm2 is markedly increased indicating that the expression of Mdm2 indeed destabilises E7. In the case of the Mdm2 interaction with E2, we observe that E2 inhibits Mdm2 mediated degradation of p53 and pRB and that the expression of Mdm2 enhances E2’s transcriptional activity and induces its re-localisation at specific structures within the nucleus. Overall, our findings expand our knowledge of the regulation of virally encoded proteins both through direct protein-protein interactions between themselves and through their interactions with cellular proteins.

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