Figure 6.

Proposed model for the modulation of keratinocyte cell fate based on the inactivation of p53 and Notch by E6 expression. (A) Homeostasis in the squamous epithelium is determined by the balanced probability of the outcome of each cell division: two differentiating cells, one differentiating and one proliferating progenitor, and two proliferating progenitors (left panel). According to this model, the fate of each division is stochastic; however, across the total population, the odds of having one of the three possible outcomes is balanced. As a result, in the basal layer the proliferation of progenitor cells (red cells with circles) compensates for the loss of cells by terminal differentiation (green cells with arrowhead). (B) Upon infection with HPV‐16, the inactivation of p53 and Notch leads to an unbalanced fate of cell divisions, with a skew towards proliferation (left panel). In low‐grade lesions (upper‐right panel), reduced levels of p53 and Notch in HPV‐infected (purple) cells allow for the maintenance and expansion of the HPV‐infected pool in the basal layer. However, low levels of E6 and E7 expression allow for an adequate level of keratinocyte differentiation able to sustain the viral life cycle. Its deregulation (lower‐right panel) is thought to be associated with an elevation of E6 and E7 expression. Increased E6 levels further reduce the proportion of differentiating cells within the infected basal cell population, allowing for their clonal expansion and persistence with the colonization of large areas of the epithelium. Increased levels of proliferation and long‐term persistence in the epithelium may eventually lead to the accumulation of oncogenic mutations (cells with dark purple nuclei) predisposing to the development of malignancy.