AbstractEarly growth response‐1 (EGR‐1), one of immediate early response genes, is involved in diverse cellular response. We recently reported that quercetin increased catalytic subunit of γ‐glutamylcysteine ligase (GCLC) via the interaction of EGR‐1 to GCLC promoter in INS‐1 beta‐cells. Therefore, this study investigated molecular mechanisms of quercetin‐induced EGR‐1 expression in INS‐1 cells. Quercetin significantly induced EGR‐1 protein and its mRNA expressions. This induction of EGR‐1 was completely blocked by pretreatment with a PKA inhibitor, H89 and partially blocked by a p38 inhibitor, SB203580. Additionally, the siRNA‐mediated inhibition of PKAα and p38 resulted in significant reduction of quercetin‐induced EGR‐1 promoter activity. Also, quercetin‐induced EGR‐1 protein expression was significantly decreased in the cells transfected with PKAα siRNA. Study using truncated EGR‐1 promoter constructs showed that serum response element (SRE) sites, not cAMP response element site, were essential for EGR‐1 transcription. However, electrophoretic mobility shift assay showed that quercetin did not affect the band intensity of DNA‐protein complex on SRE site of EGR‐1 promoter. Also, immune‐shift assay using serum response factor (SRF) and phospho‐SRF antibodies showed no difference between control and quercetin‐treated groups. Collectively, quercetin‐induced EGR‐1 expression is largely dependent on PKA and partly on p38 MAPK pathway, and SRE sites of EGR‐1 promoter are involved in quercetin‐induced EGR‐1 transcriptional activity. J. Cell. Biochem. 113: 1559–1568, 2012. © 2011 Wiley Periodicals, Inc.