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Vol. 19, Issue 8, 3263-3271, August 2008

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The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

Jennifer L. Marlowe^*, Yunxia Fan, Xiaoqing Chang, Li Peng, Erik S. Knudsen, Ying Xia, and Alvaro Puga

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056

Submitted April 6, 2008; Revised May 8, 2008; Accepted May 23, 2008
Monitoring Editor: William P. Tansey

Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr^–/– fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, H2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RB-negative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G₀/G₁ cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression.

Present addresses: * Novartis Pharma AG, CH-4132 Muttenz, Switzerland;

Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.

Address correspondence to: Alvaro Puga (alvaro.puga{at}uc.edu)