Page 14 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 1
replication. The E6 protein binds and degrades the host tumor suppressor protein p53, causing diminished cell-cycle blockade and apoptosis.[3, 8] These processes have been depicted in figure 1.
Figure 1. Cellular processes in cervical carcinogenesis following HPV infection.
E6 acts through inhibition of p53, a well-known inductor of apoptosis. Additionally, E6 leads to the increase of telomerase activity by activation of transcription of telomerase reverse transcriptase, leading to sustained telomerase, necessary for cell immortalization. E7 inactivates tumour suppressor protein retinoblastoma (Rb), thereby increasing free E2F, leading to cellular proliferation. Cells in which the normal actions of Rb are suppressed by E7 are characterized by an increased expression of proliferation markers, such as Ki67, and increased expression of p16. P16 is a protein that promotes cell cycle arrest through prevention of hyperphosphorylation of Rb. However, its function is bypassed by HPV, because binding of E7 to pRb creates a phosphorylation independent release of E2F. The combined action of E6 and E7 proteins stimulate S-phase cell cycle entry and surpassing of cell cycle checkpoints, leading to cell proliferation and immortalization. With additional accumulation of genomic instability, this forms the basis for cervical cancer development.
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