No abstract

Epstein-Barr virus, a ubiquitous human herpesvirus, is associated with the development of carcinomas and lymphomas. We previously showed that transforming growth factor ␤1 (TGF-␤1) mediated the virus to enter the lytic cycle, which is triggered by expression of Z Epstein-Barr virus replication activator (ZEBRA), through the ERK 1/2 MAPK signaling pathway. We report here that Akt, activated downstream from ERK 1/2, was required for TGF-␤1-induced ZEBRA expression and enabled Smad3, a mediator of TGF-␤1 signaling, to be acetylated by direct interaction with the co-activator CREB-binding protein and then to regulate TGF-␤1-induced ZEBRA expression.

Transforming growth factor beta 1 (TGF-␤1) signal transduction has been implicated in many secondmessenger pathways, including the NF-B pathway. We provide evidence of a novel TGF-␤1-mediated pathway that leads to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, which in turn induces expression of an Epstein-Barr virus (EBV) protein, ZEBRA, that is responsible for the induction of the viral lytic cycle. This pathway includes two unexpected steps, both of which are required to control ERK 1/2 phosphorylation: first, a quick and transient activation of NF-B, and second, downregulation of inducible nitric oxide synthase (iNOS) activity that requires the participation of NF-B activity. Although necessary, NF-B alone is not sufficient to produce downregulation of iNOS, suggesting that another uncharacterized event(s) is involved in this pathway. Dissection of the steps involved in the switch from the EBV latent cycle to the lytic cycle will be important to understand how virus-host relationships modulate the innate immune system.