Unique and overlapping transcriptional roles of arylhydrocarbon receptor nuclear translocator (Arnt) and Arnt2 in xenobiotic and hypoxic responses

Hiroki Sekine, Junsei Mimura, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Arnt and the homologous Arnt2 share a high degree of sequence similarity and are believed to function as obligate common partners for a number of basic helix-loop-helix (bHLH)-PAS transcription factors including arylhydrocarbon receptor (AhR) and HIFα. Genetic disruption of both Arnt and Arnt2 demonstrated both unique and overlapping functions in response to environmental stimuli and during mouse development. Either stably or transiently expressed Arnt/Arnt2 wild type and various mutants or chimeric constructs in Hepa1-c4 cells exhibit similar levels of hypoxic response element-driven reporter gene expression and the induction of endogenous Glut-1 through binding with HIFα in response to hypoxia. In contrast, we observed clear functional differences in the ability of Arnt and Arnt2 to induce xenobiotic response element-driven reporter and endogenous CYP1A1 gene expression. In contrast with Arnt, Arnt2 was practically incapable of interacting with ligand-activated AhR to induce the expression of target genes for xenobiotic-metabolizing enzymes in response to xenobiotics. The differential binding of AhR by Arnt and Arnt2 can be ascribed to a single His/Pro amino acid difference in the PASB region of Arnt and Arnt2, suggesting that the PASB/PASB interaction between bHLH-PAS transcription factors plays a selective role for their specific partner molecule.

Original languageEnglish
Pages (from-to)37507-37516
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number49
DOIs
Publication statusPublished - 2006 Dec 8
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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