Fig. 1
Simplified illustration showing biomarkers of cervical neoplasia and their effects on the cell cycle. a Normal epithelium: external growth factors activate the cyclin D1/CDK4/6 complex, which in turn hyperphosphorylates pRb. E2F is released and activates genes for S-phase progression. Among these genes are p16INK4A and p14ARF. A p16INK4A-induced feedback mechanism inactivates cyclin D1/CDK4/6 complexes and inactivates E2F. p14ARF controls p53 levels in the cell and activates p21, which is a CDK inhibitor. b HPV-infected epithelium: HPV oncogene E7 binds to and inactivates pRB releasing active E2F in basal as well as para-basal cell layers. There, E2F induces S-phase genes. Importantly, the p16INK4A feedback loop is bypassed leading to prolonged E2F activity. p14ARF over-expression results in inactivation of MDM2, which can no longer regulate p53 levels. HPV oncogene E6 binds p53 and targets it for degradation resulting in the suppression of p53 target genes.