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 E pstein-Barr virus gene expression that culminates in virus production, Zta is a sequence-specific DNA-binding protein that transactivates ea rly viral promoters via cis-acting sequences. Activation of some of th ese genes is mediated through binding to consensus AP-1 promoter eleme nts. This observation suggests that Zta may also regulate the expressi on of cellular genes. While many targets of Zta have been identified i n the Epstein-Barr virus genome, putative host cell targets remain lar gely unknown. To address this issue, a tetracycline-regulated Zta expr ession system was generated, and differential hybridization screening was used to isolate Zta-responsive cellular genes, The major target id entified by this analysis is a gene encoding a fasciclin-like secreted factor, transforming growth factor beta igh3 (TGF beta igh3), that wa s originally identified as a gene that is responsive to the potent imm unosuppressor TGF-beta 1. Northern (RNA) blot analysis demonstrated th at induction of Zta expression results in a 10-fold increase in TGF-be ta igh3 mRNA levels. Zta was also found to increase TGF-beta 1 mRNA le vels as well as the amount of active TGF-beta 1 secreted into the medi um, Interestingly, alpha 1-collagen IV, which has been shown to potent iate the effects of TGF-beta 1, is also a cellular target of Zta, Thes e results suggest that Zta could play a role in modulating the host ce ll environment through activating the expression of secreted factors.