EGR1, EGR2, and EGR3 Activate the Expression of Their Coregulator NAB2 Establishing a Negative Feedback Loop in Cells of Neuroectodermal and Epithelial Origin

The inducible zinc finger transcription factors EGR1. EGR2, and EGR3 regulate the expression of numerous genes involved in differentiation, growl h. and response to extracellular signals. Their activity is modulated in part through NAB2 which is induced by the same stimuli In melanoma and carcinoma cells EGR 1 activates NAB2 expression In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression Therefore, we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells Here, we show that like EGR I. EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NA82 promoter and are mote potent activators of NAB2 transcription than EGR2 EGR EGR2-, and EGR3-induced NAB2 promoter activity is mediated through similar cis-regulatory elements and the activation by each EGR is repressed by NAB2 Kinetic studies suggest that induction of EGR I leads to low NAB2 expression, while EGR2 and EGR3 are necessary for maximal and sustained expression. As already shown (or EGR 1, reduction of EGR2 or EGR 3 expression by siRNAs reduced endogenous NA82 levels Depletion of EGR3 also resulted in a reduction of EGR2 levels confirming EGR2 as a target gene of EGR3 Our results suggest that in many cells of neuroeciodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcnption which is in turn repressed by NAB2, thus establishing a negative feedback loop This points to a complex relationship between the EGR factors and NAB2 expression likely depending on the cellular context. J Cell. Biochem 111. 207-217, 2010. (C) 2010 Wiley-Liss, Inc