Phospho-Regulation of Cancer Causing Human Papillomavirus (HPV) E6 Oncoproteins

Boon, Siaw Shi (2014). Phospho-Regulation of Cancer Causing Human Papillomavirus (HPV) E6 Oncoproteins. PhD thesis The Open University.



Cervical cancer develops through the combined activity of the Human Papillomavirus (HPV) E6 and E7 oncoproteins. A defining characteristic of the E6 oncoproteins derived from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at the extreme carboxy terminus of the protein, which is absent from E6 proteins derived from the so-called low risk (LR) HPV types. This PDZ binding potential of the high risk (HR) HPV E6 oncoproteins is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions can be negatively regulated by phosphorylation within the E6 PBM. In this study, I have investigated the differential regulation of diverse HR HPV E6 PBMs. Depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with PKA or AKT. This in turn inhibits PDZ recognition whilst conferring direct association with 14-3-3 family members. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18 and HPV-58, whilst being somewhat weaker or absent from other types such as HPV-31, -33 and -51. Phosphorylation is important for maintaining the steady state levels of HPV-18 E6 and this is also can be affected by its association with 14-3-3. I also show that HPV-18 E6 phosphorylation occurs primarily during the G2/M phase of the cell cycle whereas HPV-16 E6 phosphorylation occurs during S phase. This cell cycle-dependent phosphorylation in turn regulates the levels of E6 expression and confers enhanced interaction with multiple 14-3-3 isoforms. E6 does not degrade 14-3-3, but it alters the subcellular distribution of 14-3-3 and as a consequence, inhibits p53/14-3-3 transcriptional transctivation in an E6 PBM dependent manner. These studies reveal unexpected differences in the regulation of HPV-16 and HPV-18 E6 function and have important implications for how phosphorylation of E6 might be expected to play a role during the respective viral life cycles and tumour development.

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