The tumor suppressor kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner

Shelly R. Wilson, Aditya D. Joshi, Cornelis Elferink

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-mediated basic helix-loop-helix transcription factor of the Per/Arnt/Sim family that regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Ligand activation leads to AhR nuclear translocation and binding to a xenobiotic response element (XRE) in association with the Arnt to regulate gene expression. Several recent genome-wide transcriptional studies identified numerous AhR target genes that lack the canonical XRE recognition site in the promoter regions. Characterization of one such target gene, the plasminogen activator inhibitor 1, identified a novel nonconsensus XRE (NC-XRE) that confers TCDD responsiveness independently of the Arnt protein. Studies reported here show that the NC-XRE is a recognition site for the AhR and a new binding partner, the Kruppel-like factor (KLF) family member KLF6. In vivo chromatin immunoprecipitations and in vitro DNA binding studies demonstrate that the AhR and KLF6 proteins form an obligatory heterodimer necessary for NC-XRE binding. Mutational analyses show that the protein-protein interactions involve the AhR C terminus and KLF6 N terminus, respectively. Moreover, NC-XRE binding depends on the 59 basic region in KLF6 rather than the previously characterized zinc finger DNA binding domain. Collectively, the results unmask a novel AhR signaling mechanism distinct from the canonical XREdriven process that will enrich our future understanding of AhR biology.

Original languageEnglish (US)
Pages (from-to)419-429
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume345
Issue number3
DOIs
StatePublished - Jun 2013

Fingerprint

Kruppel-Like Transcription Factors
Aryl Hydrocarbon Receptors
DNA
Neoplasms
Response Elements
Xenobiotics
Proteins
Halogenated Hydrocarbons
Ligands
Basic Helix-Loop-Helix Transcription Factors
Aromatic Hydrocarbons
Chromatin Immunoprecipitation
Poisons
Plasminogen Activator Inhibitor 1
Polycyclic Aromatic Hydrocarbons
Zinc Fingers
Genetic Promoter Regions
Genes
Genome
Gene Expression

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

The tumor suppressor kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. / Wilson, Shelly R.; Joshi, Aditya D.; Elferink, Cornelis.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 345, No. 3, 06.2013, p. 419-429.

Research output: Contribution to journalArticle

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