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PMID: 17709388 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis.

Molecular and cellular biology ·Vol. 27 ·No. 20 ·2007-10-00 ·Pages 7188-97

Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, Kensler TW

Abstract

The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are transcription factors controlling pathways modulating xenobiotic metabolism. AHR has recently been shown to affect Nrf2 expression. Conversely, this study demonstrates that NRF2 regulates expression of Ahr and subsequently modulates several downstream events of the AHR signaling cascade, including (i) transcriptional control of the xenobiotic metabolism genes Cyp1a1 and Cyp1b1 and (ii) inhibition of adipogenesis in mouse embryonic fibroblasts (MEFs). Constitutive expression of AHR was affected by Nrf2 genotype. Moreover, a pharmacological activator of NRF2 signaling, CDDO-IM {1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole}, induced Ahr, Cyp1a1, and Cyp1b1 transcription in Nrf2+/+ MEFs but not in Nrf2-/- MEFs. Reporter analysis and chromatin immunoprecipitation assay revealed that NRF2 directly binds to one antioxidant response element (ARE) found in the -230-bp region of the promoter of Ahr. Since AHR negatively controls adipocyte differentiation, we postulated that NRF2 would inhibit adipogenesis through the interaction with the AHR pathway. Nrf2-/- MEFs showed markedly accelerated adipogenesis upon stimulation, while Keap1-/- MEFs (which exhibit higher NRF2 signaling) differentiated slowly compared to their congenic wild-type MEFs. Ectopic expression of Ahr and dominant-positive Nrf2 in Nrf2-/- MEFs also substantially delayed differentiation. Thus, NRF2 directly modulates AHR signaling, highlighting bidirectional interactions of these pathways.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,metabolism Adipocytes/physiology Adipogenesis/physiology Animals Cell Differentiation/physiology Cells, Cultured Cytoskeletal Proteins/genetics,metabolism Fibroblasts/cytology,physiology Gene Expression Regulation Genes, Reporter Kelch-Like ECH-Associated Protein 1 Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2/genetics,metabolism Promoter Regions, Genetic Receptors, Aryl Hydrocarbon/genetics,metabolism Signal Transduction/physiology Transcription, Genetic
Chemicals
Adaptor Proteins, Signal Transducing Cytoskeletal Proteins Keap1 protein, mouse Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 Receptors, Aryl Hydrocarbon
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Shin Soona
Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
Wakabayashi Nobunao
Misra Vikas
Biswal Shyam
Lee Gum Hwa
Agoston Elin S
Yamamoto Masayuki
Kensler Thomas W
References (51)
51 references, click to expand
  1. Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes.
    Drug Metab Dispos. 1995 Jun;23(6):642-50 PMID: 7587946
  2. Aryl hydrocarbon receptor-mediated induction of microsomal drug-metabolizing enzyme activity by indirubin and indigo.
    Biochem Biophys Res Commun. 2004 May 28;318(2):571-8 PMID: 15120638
  3. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids.
    Mol Cell Biol. 1996 Aug;16(8):4128-36 PMID: 8754811
  4. Ah receptor regulation of CYP1B1 expression in primary mouse embryo-derived cells.
    Cancer Res. 1997 Oct 15;57(20):4498-506 PMID: 9377560
  5. Understanding adipocyte differentiation.
    Physiol Rev. 1998 Jul;78(3):783-809 PMID: 9674695
  6. The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-beta and apoptosis.
    Mol Pharmacol. 1998 Aug;54(2):313-21 PMID: 9687573
  7. Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis.
    J Cell Sci. 1998 Nov;111 ( Pt 22):3311-22 PMID: 9788873
  8. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.
    Genes Dev. 1999 Jan 1;13(1):76-86 PMID: 9887101
  9. Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor.
    Arch Biochem Biophys. 2005 Jan 15;433(2):379-86 PMID: 15581594
  10. Ah receptor signals cross-talk with multiple developmental pathways.
    Biochem Pharmacol. 2005 Jan 15;69(2):199-207 PMID: 15627472
  11. The role of MAPKs in adipocyte differentiation and obesity.
    Biochimie. 2005 Jan;87(1):51-6 PMID: 15733737
  12. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.
    J Biol Chem. 2005 May 27;280(21):20340-8 PMID: 15790560
  13. The transcriptional basis of adipocyte development.
    Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):31-4 PMID: 15936931
  14. Aryl hydrocarbon receptor activation by cAMP vs. dioxin: divergent signaling pathways.
    Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9218-23 PMID: 15972329
  15. Differentiation of pluripotent C3H10T1/2 cells rapidly elevates CYP1B1 through a novel process that overcomes a loss of Ah Receptor.
    Arch Biochem Biophys. 2005 Jul 15;439(2):139-53 PMID: 15967407
  16. Comparative microarray analysis of basal gene expression in mouse Hepa-1c1c7 wild-type and mutant cell lines.
    Toxicol Sci. 2005 Aug;86(2):342-53 PMID: 15888666
  17. Induction of phase-1 metabolizing enzymes by oltipraz, flavone and indole-3-carbinol enhance the formation and transport of benzo[a]pyrene sulfate conjugates in intestinal Caco-2 cells.
    Toxicol Lett. 2005 Aug 14;158(2):140-51 PMID: 15890477
  18. The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells.
    Oncogene. 2005 Nov 24;24(53):7869-81 PMID: 16091746
  19. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity.
    Biochem Biophys Res Commun. 2006 Jan 6;339(1):79-88 PMID: 16293230
  20. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1.
    Mol Cell Biol. 2006 Jan;26(1):221-9 PMID: 16354693
  21. Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries.
    Mol Pharmacol. 2006 Jan;69(1):140-53 PMID: 16214954
  22. Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
    Cell Metab. 2006 Mar;3(3):211-22 PMID: 16517408
  23. Systems analyses characterize integrated functions of biochemical networks.
    Trends Biochem Sci. 2006 May;31(5):284-91 PMID: 16616498
  24. Transcription factors in asthma: are transcription factors a new target for asthma therapy?
    Curr Drug Targets. 2006 May;7(5):589-95 PMID: 16719769
  25. A cell-based system to identify and characterize the molecular mechanism of drug-metabolizing enzyme (DME) modulators.
    Biochem Pharmacol. 2004 May 15;67(10):1897-905 PMID: 15130766
  26. Sequential gene promoter interactions of C/EBPbeta, C/EBPalpha, and PPARgamma during adipogenesis.
    Biochem Biophys Res Commun. 2004 Jun 18;319(1):235-9 PMID: 15158467
  27. New insights into inhibitors of adipogenesis.
    Curr Opin Lipidol. 2004 Jun;15(3):303-7 PMID: 15166786
  28. Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism.
    Mol Cell Biol. 2004 Jun;24(12):5209-22 PMID: 15169886
  29. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element.
    Proc Natl Acad Sci U S A. 1990 Aug;87(16):6258-62 PMID: 2166952
  30. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.
    Annu Rev Pharmacol Toxicol. 2007;47:89-116 PMID: 16968214
  31. Nuclear receptor-mediated transcriptional regulation in Phase I, II, and III xenobiotic metabolizing systems.
    Drug Metab Pharmacokinet. 2006 Dec;21(6):437-57 PMID: 17220560
  32. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.
    Mol Cancer Ther. 2007 Jan;6(1):154-62 PMID: 17237276
  33. Chemopreventive promise of targeting the Nrf2 pathway.
    Drug News Perspect. 2007 Mar;20(2):109-17 PMID: 17440634
  34. Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2.
    Biochem Pharmacol. 2007 Jun 15;73(12):1853-62 PMID: 17266942
  35. Exploring genetic interactions and networks with yeast.
    Nat Rev Genet. 2007 Jun;8(6):437-49 PMID: 17510664
  36. Plasticity in cell defence: access to and reactivity of critical protein residues and DNA response elements.
    J Exp Biol. 2006 Jun;209(Pt 12):2337-43 PMID: 16731810
  37. Global genetic regulatory networks controlling hematopoietic cell fates.
    Curr Opin Hematol. 2006 Jul;13(4):229-36 PMID: 16755218
  38. Activation of coupled Ah receptor and Nrf2 gene batteries by dietary phytochemicals in relation to chemoprevention.
    Biochem Pharmacol. 2006 Sep 28;72(7):795-805 PMID: 16780804
  39. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis.
    Biochem Pharmacol. 2000 Jan 1;59(1):65-85 PMID: 10605936
  40. Transcriptional regulation of adipogenesis.
    Genes Dev. 2000 Jun 1;14(11):1293-307 PMID: 10837022
  41. Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin.
    J Cell Sci. 2001 Aug;114(Pt 15):2809-17 PMID: 11683414
  42. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.
    Mol Cell Biol. 2002 May;22(9):2883-92 PMID: 11940647
  43. Adipogenesis and fat-cell function in obesity and diabetes.
    Trends Mol Med. 2002 Sep;8(9):442-7 PMID: 12223316
  44. A new mathematical model for relative quantification in real-time RT-PCR.
    Nucleic Acids Res. 2001 May 1;29(9):e45 PMID: 11328886
  45. Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse.
    Biochem Biophys Res Commun. 2003 Mar 28;303(1):105-11 PMID: 12646173
  46. Transcriptional regulation of the AhR gene during adipose differentiation.
    Biol Pharm Bull. 2003 Sep;26(9):1266-71 PMID: 12951469
  47. Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induced adipocyte differentiation in mouse embryonic fibroblasts (MEFs) involves tyrosine kinase c-Src.
    Biochem Pharmacol. 2003 Oct 1;66(7):1231-44 PMID: 14505802
  48. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation.
    Nat Genet. 2003 Nov;35(3):238-45 PMID: 14517554
  49. Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction.
    Biochem J. 2004 Jan 1;377(Pt 1):205-13 PMID: 14510636
  50. Modulation of AhR-mediated CYP1A1 mRNA and EROD activities by 17beta-estradiol and dexamethasone in TCDD-induced H411E cells.
    Toxicol Sci. 2004 Mar;78(1):41-9 PMID: 14691211
  51. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development.
    Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6731-6 PMID: 8692887
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00915-07
Published
2007-10-00
Epub
2007-00-20
Pages
7188-97
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2168916
Subset
IM
Grants
NHLBI NIH HHS · R01 HL081205-03 · United States
NCI NIH HHS · R01 CA094076 · United States
NHLBI NIH HHS · R01 HL081205 · United States
NIEHS NIH HHS · ES03819 · United States
NHLBI NIH HHS · HL081205 · United States
NCI NIH HHS · CA94076 · United States
NIEHS NIH HHS · P30 ES003819 · United States
External Links
PubMed source DOI: 10.1128/MCB.00915-07 PMC Full Text View journal details
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