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The Tyr705 STAT3 constitutive activation, besides promoting PEL cell survival, contributes to the maintenance of viral latency. We found indeed that its de-phosphorylation by AG490 induced KSHV lytic cycle. Moreover, Tyr705 STAT3 de-phosphorylation, mediated by the activation of tyrosine phosphatases, together with the increase of Ser727 STAT3 phosphorylation contributed to KSHV lytic cycle induction by TPA. We then observed that p53-p21 axis, essential for the induction of KSHV replication, was activated by the inhibition of Tyr705 and by the increase of Ser727 STAT3 phosphorylation. As a possible link between STAT3, p53-p21 and KSHV lytic cycle, we found that TPA and AG490 reduced the expression of KAP-1, promoting p53 stability, p21 transcription and KSHV lytic cycle activation in PEL cells.

The switch from latency to lytic phase of Epstein–Barr virus (EBV) is coordinated by the expression of two viral transactivators known as ZEBRA and RTA. The BFRF1 gene has been shown to be transcribed during the early phases of EBV lytic cycle. Here, we characterized the BFRF1 promoter showing that ZEBRA transfection stimulated BFRF1 expression, whereas RTA induced BFRF1 only after the transfection of an amount of plasmid largely in excess than that sufficient to stimulate the expression of other RTA-responsive genes. However, a co-operative effect between ZEBRA and RTA in the expression of BFRF1 is evident since the transfection of RTA can rescue the transactivating capacity of a mutant of the ZEBRA protein, known as Z(S186A), that has a substitution affecting the DNA binding region. Moreover, we identified one ZEBRA-responsive element (ZRE) and one RTA-responsive element (RRE) within the BFRF1 promoter region.