IDENTIFICATION OF CELLULAR TARGET GENES OF THE EPSTEIN-BARR-VIRUS TRANSACTIVATOR ZTA - ACTIVATION OF TRANSFORMING GROWTH-FACTOR BETA-IGH3 (TGF-BETA-IGH3) AND TGF-BETA-1

The lytic switch transactivator Zta initiates the ordered cascade of Epstein-Barr virus gene expression that culminates in virus production, Zta is a sequence-specific DNA-binding protein that transactivates early viral promoters via cis-acting sequences. Activation of some of these genes is mediated through binding to consensus AP-1 promoter elements. This observation suggests that Zta may also regulate the expression of cellular genes. While many targets of Zta have been identified in the Epstein-Barr virus genome, putative host cell targets remain largely unknown. To address this issue, a tetracycline-regulated Zta expression system was generated, and differential hybridization screening was used to isolate Zta-responsive cellular genes, The major target identified by this analysis is a gene encoding a fasciclin-like secreted factor, transforming growth factor beta igh3 (TGF beta igh3), that was originally identified as a gene that is responsive to the potent immunosuppressor TGF-beta 1. Northern (RNA) blot analysis demonstrated that induction of Zta expression results in a 10-fold increase in TGF-beta igh3 mRNA levels. Zta was also found to increase TGF-beta 1 mRNA levels as well as the amount of active TGF-beta 1 secreted into the medium, Interestingly, alpha 1-collagen IV, which has been shown to potentiate the effects of TGF-beta 1, is also a cellular target of Zta, These results suggest that Zta could play a role in modulating the host cell environment through activating the expression of secreted factors.