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Activating Transcription Factor 3 Is a Novel Repressor of the Nuclear Factor Erythroid-Derived 2–Related Factor 2 (Nrf2)–Regulated Stress Pathway

Department of Radiation Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Michael L. Freeman, Radiation Oncology, Vanderbilt University School of Medicine, B 902 TVC, Nashville, TN 37232. Phone: 615-322-3606; Fax: 615-343-3061; E-mail: michael.freeman{at}vanderbilt.edu.

The transcription factor nuclear factor erythroid-derived 2–related factor 2 (Nrf2) regulates induction of an extensive cellular stress response network when complexed with the cAMP-responsive element binding protein (CBP) at antioxidant response elements (ARE) located in the promoter region of target genes. Activating transcription factor 3 (ATF3) can repress Nrf2-mediated signaling in a manner that is not well understood. Here, we show that ATF3-mediated suppression is a consequence of direct ATF3-Nrf2 protein-protein interactions that result in displacement of CBP from the ARE. This work establishes ATF3 as a novel repressor of the Nrf2-directed stress response pathway. [Cancer Res 2008;68(2):364–8]