Figure 2.

HPyVs’ large tumor antigen (LT-Ag) oncogenic mechanisms. (A) In physiological conditions, the retinoblastoma proteins (pRbs) are in a hypophosphorylated state, which allows them to bind and inhibit the E2F transcription factors, preventing the E2F-mediated gene expression and consequently the transition from G₁ to S phase. HPyVs’ LT-Ag is able to bind the pRbs promoting their hyperphosphorylation, thus pRb is unable to bind E2F, leading to its transcriptional activity; at the same time, the hyperphosphorylation of p130 disrupts the transcriptional repressor complex (p130-E2F4/5), leading to uncontrolled cell cycle progression and sometimes to malignant transformation. (B) Multiple cellular stress, normally, raises the levels of p53, which promotes the DNA repair and cell cycle arrest. HPyVs’ LT-Ag is able to bind and block the activity of p53 protein, preventing apoptosis and cell cycle arrest induced by DNA damage. (C) In physiological conditions, the phosphorylated β-catenin undergoes degradation via ubiquitin-dependent proteasome. JCPyVs’ LT-Ag binds the β-catenin protein promoting its hypophosphorylation, thus β-catenin complexes with LEF-1/TCF-4 transcription factors, promoting the cell cycle progression by c-myc and cyclin D1 expression. HPyVs indicate human polyomaviruses; JCPyV, human JC polyomavirus.