Figure 7. Roles of KSHV vFLIP and vCyclin, and HTLV-1 Tax in oncogenesis.

(A) Synergistic actions of KSHV latency proteins vCyclin and vFLIP Cells latently infected by KSHV express vCyclin and vFLIP from a bicistronic latency mRNA transcript. NF-κB hyper-activation by vFLIP promotes cell survival, but triggers a host checkpoint response mediated by p21 and p27 that arrests cells in the G1 phase of the cell cycle. KSHV vCyclin binds and activates Cdk6 to promote S phase entry. The vCyclin/Cdk6 complex prevents the G1 arrest caused by vFLIP, thereby facilitating chronic NF-κB activation and cell survival. However, vCyclin expression also causes DNA hyper-replication and activates the DNA damage response or other checkpoints, which likely become inactivated by other viral factors or cellular oncogenic alterations. (B) In HTLV-1 transformed cells, the senescence checkpoint response induced by Tax is inactivated by deregulation of G1 Cdks and Cdk inhibitors p21 and p27. Hyper-activation of IKK/NF-kB by the HTLV-1 triggers cellular senescence checkpoint response, which is likely mitigated by somatic mutations that deregulate G1 Cdks and G1 Cdk inhibitors.