p16^INK4A and p14^ARF Gene Promoter Hypermethylation as Prognostic Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma: A Review

Figure 1

Cell cycle arrest by CDKN2A. The CDKN2A gene encodes two alternatively spliced transcripts, p16^INK4A and p14^ARF, which differ in their first exon. The p16^INK4A protein inhibits the CDK4/6-cyclin D1 complexes, keeping the retinoblastoma (Rb) proteins in a dephosphorylated state, and enables binding and inactivating the E2F transcription factors. Free E2F ensures the transcription of various proteins, most of them are necessary for progression to S phase. P16^INK4A is also upregulated by E2F. In contrast, p14^ARF stabilizes and thus activates the tumor suppressor gene p53 by inhibiting MDM2, which inactivates p53 by ubiquitin-mediated degradation. Active p53 induces the expression of p21, a negative cell cycle regulator which is an inhibitor of the CDK1-cyclin A/B complexes, thereby preventing the progression from G2 phase to metaphase. The human papillomavirus oncoproteins E6 and E7 interfere in the Rb pathway and in the p53 pathway, in order to bypass the cell cycle checkpoints. The E7 oncoprotein promotes the progression to S phase. It binds the Rb proteins and thereby releases the E2F transcription factors. The E6 protein targets p53 and induces loss of function by degradation.