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Publication Detail

Title: The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis.

Authors: Marlowe, Jennifer L; Fan, Yunxia; Chang, Xiaoqing; Peng, Li; Knudsen, Erik S; Xia, Ying; Puga, Alvaro

Published In Mol Biol Cell, (2008 Aug)

Abstract: 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, gammaH2A.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-G(0)/G(1) 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.

PubMed ID: 18524851 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis*; Apoptotic Protease-Activating Factor 1/metabolism; Cell Cycle; Cell Line, Tumor; E2F1 Transcription Factor/metabolism*; Fibroblasts/metabolism; Histones/metabolism; Humans; Mice; Models, Biological; Oxidative Stress*; Promoter Regions, Genetic; Receptors, Aryl Hydrocarbon/metabolism*

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