Received for publication May 19, 2005.
Revised July 7, 2005.
Accepted for publication July 28, 2005.

Transcriptional Regulation of Activating Transcription Factor 3 (ATF3) Involves the Early Growth Response-1 (Egr-1) Gene

Abstract

Previously, our laboratory identified Activating Transcription Factor 3 (ATF3) as up-regulated by non- steroidal anti-inflammatory drugs (NSAIDs) using microarray analysis of mRNA from human colorectal cancer cells treated with sulindac sulfide. ATF3 is a transcription factor involved in cell growth, apoptosis, and invasion, and is induced by a variety of anti-cancer and dietary compounds. However, the regulation of ATF3 by anti-cancer agents is not known. The promoter of ATF3 contains several transcription factor binding sites. We identified three putative Egr-1 binding sites in the promoter of ATF3 and report for the first time that the molecular mechanism responsible for the transcriptional regulation of ATF3 by two divergent pharmaceutical compounds sulindac sulfide and troglitazone, involved the early growth response gene-1 (Egr-1). For example, overexpression of Egr-1 protein induced ATF3 mRNA 3.5-fold and transcriptional activity of an ATF3 promoter construct more than 20-fold. ATF3 and Egr-1 mRNA and protein and ATF3 promoter activity were induced by these compounds, whereas induction of ATF3 by these compounds was blocked by Egr-1 small interfering RNA. Sulindac sulfide and troglitazone regulated ATF3 promoter activity, which was suppressed when the two Egr-1 sites were mutated. These compounds induced phosphorylation of extracellular regulated kinase1/2 (Erk1/2) while a dominant negative inhibitor of MEK1 blocked the induction of ATF3. The MEK1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked the induction of ATF3 and Egr-1 mRNA expression and ATF3 promoter activity by these compounds. Therefore, this is a novel, first report demonstrating that the expression of ATF3 occurs via Egr-1 downstream of Erk1/2.

Key words: ATF3, NSAIDs, colorectal cancer, cyclooxygenase, sulindac sulfide, tumorigenesis

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