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, Alvaro Puga

Research output: Contribution to journalArticle

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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, γH2A.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.

Original languageEnglish (US)
Pages (from-to)3263-3271
Number of pages9
JournalMolecular Biology of the Cell
Volume19
Issue number8
DOIs
StatePublished - Aug 2008

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Aryl Hydrocarbon Receptors
Checkpoint Kinase 2
E2F1 Transcription Factor
Apoptosis
Retinoblastoma Protein
Binding Sites
Phosphorylation
Ligands
Doxycycline
Chromatin Immunoprecipitation
Etoposide
Histones
Small Interfering RNA
DNA Damage
Oxidative Stress
Cell Death
Fibroblasts
Messenger RNA
Genes
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Marlowe, J. L., Fan, Y., Chang, X., Peng, L., Knudsen, E. S., Xia, Y., & Puga, A. (2008). The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Molecular Biology of the Cell, 19(8), 3263-3271. https://doi.org/10.1091/mbc.E08-04-0359

The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. / Marlowe, Jennifer L.; Fan, Yunxia; Chang, Xiaoqing; Peng, Li; Knudsen, Erik S.; Xia, Ying; Puga, Alvaro.

In: Molecular Biology of the Cell, Vol. 19, No. 8, 08.2008, p. 3263-3271.

Research output: Contribution to journalArticle

Marlowe, JL, Fan, Y, Chang, X, Peng, L, Knudsen, ES, Xia, Y & Puga, A 2008, 'The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis', Molecular Biology of the Cell, vol. 19, no. 8, pp. 3263-3271. https://doi.org/10.1091/mbc.E08-04-0359
Marlowe, Jennifer L. ; Fan, Yunxia ; Chang, Xiaoqing ; Peng, Li ; Knudsen, Erik S. ; Xia, Ying ; Puga, Alvaro. / The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. In: Molecular Biology of the Cell. 2008 ; Vol. 19, No. 8. pp. 3263-3271.
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