Figure 3. Mechanisms of simian virus 40 infection and cell transformation.

Upon SV40 entry, Tag is expressed and accumulates in the host cells, where it binds to p53, pRb, p300, p400 and possibly other proteins, to form a multiprotein complex that activates transcription of IGF-1. Tag also induces, possibly with similar mechanisms, the expression of other growth factors. (A) In the majority of infected HM, late gene transcription leads to VP1-3 viral capsid protein expression and virion assembly. Host cells undergo necrotic lysis, owing to massive viral release and a PARP-mediated mechanism. (B) In a fraction of infected HM, VP1-3 expression is blocked by the antisense mechanism [35], virions are neither assembled nor released and host cells survive. (C) In these cells, the signaling induced by the autocrine IGF-1/IGF-1R loop (and by other ligand/receptor autocrine circuits) eventually leads to G1/S progression and cell proliferation. Also tag contributes to cell survival inducing Akt activity as a consequence of PP2A inhibition. (D) Exposure to asbestos activates EGFR signaling, leading to ERK activity and AP-1 transcription, and induces programmed cell necrosis with consequent release of HMGB1 and other proinflammatory cytokines [77], leading to chronic inflammation. (E) The signaling induced by asbestos and SV40 infection, either independently or in a cooperative manner, can promote HM transformation and mesothelioma development.

EGFR: EGF receptor; HM: Human primary mesothelial cell; HMGB1: High molecular group binding protein 1; PARP: Poly (ADP-ribose) polymerase; pRb: Retinoblastoma protein; SV40: Simian virus 40; Tag: Large T antigen; tag: Small t antigen; VEGFR: VEGF receptor.