Early growth response 1 (Egr-1) is a cellular transcription factor involved in diverse biologic functions. Egr-1 has been associated with Epstein-Barr virus (EBV) infection, but it is still unknown whether any EBV protein regulates Egr-1 expression. In this study, we first showed that EBV reactivation is involved in upregulation of Egr-1 and that Egr-1 can be induced by Zta, an EBV lytic transactivator. Zta not only binds to the Egr-1 promoter but also activates the ERK signaling pathway to trigger binding of Elk-1 to the Egr-1 promoter. In addition, knockdown of Egr-1 significantly reduces the spontaneous expression of Zta and Rta in EBV-infected 293 cells, suggesting that a positive-feedback network involving Egr-1 is required for EBV reactivation. This study also implies that Zta has the potential to affect expression of certain genes through Egr-1.Early growth response 1 (Egr-1), also designated zif268, NGFI-A, and Krox24, is a cellular transcription factor belonging to a family of zinc finger DNA-binding proteins (49). According to its diverse target genes, Egr-1 has been associated with a broad range of biologic functions such as cell proliferation (3, 4, 41), apoptosis (39,51,54), and differentiation (28, 50) in a cell-type-dependent manner. Encoded by an immediate-early gene, Egr-1 can be rapidly induced by many stimuli, including growth factors, cytokines, and various stresses (6,31,44,46). Most of the stimuli trigger cellular signaling converged to mitogen-activated protein kinase (MAPK) pathways, which lead to phosphorylation and activation of a ternary complex factor, Elk-1 (26, 31, 46). Activated Elk-1 interacts with the serum response factor (SRF) to form a ternary complex that binds to a DNA element composed of a core serum response element (SRE) and the adjacent Ets motif (25, 52). There are five such binding sites for the ternary complex in the promoter of the Egr-1-encoding gene, and activation of signal transduction from MAPKs to the ternary complex is essential for Egr-1 expression induced by various stimuli (26,31,45,46).Several clues indicate that Egr-1 is also linked to infection with Epstein-Barr virus (EBV), a human gammaherpesvirus closely associated with several lymphoid and epithelial malignancies (43). First, Egr-1 is upregulated when EBV interacts with B lymphocytes at the initial infection stage, and constitutive expression of Egr-1 correlates with certain types of EBV latency in B-lymphoid cell lines (5). Notably, Egr-1 has also been associated with the lytic state of EBV infection (56). EBV reactivation into the lytic cycle is initiated from activation of two immediate-early viral promoters, Zp and Rp, which are driven to express the BZLF1 (Zta) and BRLF1 (Rta) proteins, respectively (22). Both Zta and Rta are key lytic transactivators which autostimulate their own expression, reciprocally induce each other, and cooperatively direct the downstream expression cascade of EBV lytic genes (18,20,42,48). A previous study showed that Egr-1 can activate Rp and identified two Egr-1-bindi...
