EGR1 Is a Novel Target for AhR Agonists in Human Lung Epithelial Cells

Abstract

The transcription factor early growth response 1 (EGR1) was previously identified as a potential novel target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human lung epithelial cells by toxicogenomic analysis. EGR1 has been implicated in the pathogenesis of vascular disease and is altered by a number of factors that include stress, inflammation, and hypoxia. Depending on its downstream targets or protein interactions, EGR1 regulates important biological processes that include cell growth, apoptosis, and differentiation. The following experiments were conducted to determine if EGR1 is indeed a target of TCDD and polycyclic aromatic hydrocarbons (PAHs) that can act through a similar mechanism. Pulmonary epithelial cells were exposed to TCDD for 24 h and an increase in EGR1 mRNA was measured. In addition, EGR1 protein was increased by TCDD and PAHs that have binding affinity to the aryl hydrocarbon receptor. The transcriptional activity of the EGR1 promoter was measured with a luciferase construct; however, no increases in luciferase activity were detected in TCDD or PAH-treated cells. Using actinomycin to inhibit RNA synthesis, we found that TCDD increased the half-life of EGR1 mRNA from 13 to 22 min. Thus, the increase in EGR1 expression appears to be mediated through a post-transcriptional mechanism that leads to the higher EGR1 protein levels in TCDD and PAH treated cells, compared to vehicle treated cells. Increased expression of a transcription factor EGR1 with tumorigenic and other biological activities could contribute to the deleterious pulmonary effects of exposure to these environmental agents.