Transactivators Zta and Rta of Epstein–Barr virus promote G0/G1 to S transition in Raji cells: A novel relationship between lytic virus and cell cycle

In the present study, we show that the treatment of Epstein–Barr virus (EBV) latently infected Raji cells with TPA/SB caused the cell growth arrest. The Zta-positive cells were predominantly enriched in G0/G1 phase of cell cycle. When Zta expression reached a maximal level, a fraction of Zta expressing cell population reentered S phase. Analysis of the expression pattern of a key set of cell cycle regulators revealed that the expression of Zta and Rta substantially interfered with the cell cycle regulatory machinery in Raji cells, strongly inhibiting the expression of Rb and p53 and inducing the expression of E2F1. Down-regulation of Rb was further demonstrated to be mediated by proteasomal degradation, and p53 and p21 affected at transcription level. The data indicate that both Zta and Rta promote entry into S phase of Raji cells. The important roles of Zta and Rta in EBV lytic reactivation were also demonstrated. Our finding suggests that these two transcriptional activators may act synergistically to govern the expression of downstream early and late genes as well as cellular genes and initiation of lytic cycle and manipulation of cell cycle regulatory mechanisms require the joint and interactive contributions of Rta and Zta.