Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 215–220 | Cite as

Hypoxia-Inducible Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) (HIF-1β): Is It a Rare Exception?

  • Markus Mandl
  • Reinhard Depping
Review Article

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as hypoxia-inducible factor (HIF)-1β, plays a pivotal role in the adaptive responses to (micro-)environmental stresses such as dioxin exposure and oxygen deprivation (hypoxia). ARNT belongs to the group of basic helix-loop-helix (bHLH)-Per-ARNT-Sim (PAS) transcription factors, which act as heterodimers. ARNT serves as a common binding partner for the aryl hydrocarbon receptor (AhR) as well as HIF-α subunits. HIF-α proteins are regulated in an oxygen-dependent manner, whereas ARNT is generally regarded as constitutively expressed, meaning that neither the arntmRNA nor the protein level is influenced by hypoxia (despite the name HIF-1β). However, there is emerging evidence that tumor cells derived from different entities are able to upregulate ARNT, especially under low oxygen tension in a cell-specific manner. The objective of this review is therefore to highlight and summarize current knowledge regarding the hypoxia-dependent upregulation of ARNT, which is in sharp contrast to the general point of view described in the literature. Elucidating the mechanism behind this rare cellular attribute will help us to gain new insights into HIF biology and might provide new strategies for anticancer therapeutics. In conclusion, putative treatment effects on ARNT should be taken into account while studying the HIF pathway. This step is of great importance when ARNT is intended to serve as a loading control or as a reference.

Notes

Acknowledgments

The authors thank Wolfgang Jelkmann for support and helpful discussions. The authors are grateful to Gabriela Fletschinger for help with graphic design.

M Mandl is an associated member of the Institute of Physiology at the University of Lübeck.

References

  1. 1.
    Bersten DC, Sullivan AE, Peet DJ, Whitelaw ML. (2013) bHLH-PAS proteins in cancer. Nat. Rev. Cancer. 13:827–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Urban JD, Budinsky RA, Rowlands JC. (2011) Single nucleotide polymorphisms in the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene. Drug Metab. Pharmacokinet. 26:637–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Rankin EB, Giaccia AJ. (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15:678–85.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Depping R, et al. (2007) Nuclear translocation of hypoxia-inducible factors (HIFs): involvement of the classical importin alpha/beta pathway. Biochim. Biophys. Acta. 1783:394–404.CrossRefGoogle Scholar
  5. 5.
    Ke Q, Costa M. (2006) Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol. 70:1469–80.CrossRefPubMedGoogle Scholar
  6. 6.
    Semenza GL. (2012) Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Abel J, Haarmann-Stemmann T. (2010) An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol. Chem. 391:1235–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Zagorska A, Dulak J. (2004) HIF-1: the knowns and unknowns of hypoxia sensing. Acta. Biochim. Pol. 51:563–85.PubMedGoogle Scholar
  9. 9.
    Marinkovic N, Pasalic D, Ferencak G, Grskovic B, Stavljenic Rukavina A. (2010) Dioxins and human toxicity. Arh. Hig. Rada Toksikol. 61:445–53.CrossRefPubMedGoogle Scholar
  10. 10.
    Hankinson O. (2008) Why does ARNT2 behave differently from ARNT? Toxicol. Sci. 103:1–3.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Qin XY, et al. (2011) siRNA-mediated knockdown of aryl hydrocarbon receptor nuclear translocator 2 affects hypoxia-inducible factor-1 regulatory signaling and metabolism in human breast cancer cells. FEBS Lett. 585:3310–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J. (2008) A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron. 1:53–68.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Semenza GL. (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33:207–14.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Obacz J, Pastorekova S, Vojtesek B, Hrstka R. (2013) Cross-talk between HIF and p53 as mediators of molecular responses to physiological and genotoxic stresses. Mol. Cancer. 12:93.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Semenza GL. (2010) Oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2:336–61.CrossRefPubMedGoogle Scholar
  16. 16.
    Kummar S, et al. (2011) Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1alpha in advanced solid tumors. Clin. Cancer Res. 17:5123–31.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Strofer M, et al. (2011) Stabilisation and knockdown of HIF: two distinct ways comparably important in radiotherapy. Cell Physiol. Biochem. 28:805–12.CrossRefPubMedGoogle Scholar
  18. 18.
    Ban HS, Uto Y, Nakamura H. (2011) Hypoxia-inducible factor inhibitors: a survey of recent patented compounds (2004–2010). Expert Opin. Ther. Pat. 21:131–46.CrossRefPubMedGoogle Scholar
  19. 19.
    Guerin E, et al. (2012) In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1alpha target genes and decreases tumor angiogenesis. Mol. Med. 18:83–94.CrossRefPubMedGoogle Scholar
  20. 20.
    Melillo G. (2006) Inhibiting hypoxia-inducible factor 1 for cancer therapy. Mol. Cancer Res. 4:601–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Xie J, Huang X, Park MS, Pham HM, Chan WK. (2014) Differential suppression of the aryl hydrocarbon receptor nuclear translocator-dependent function by an aryl hydrocarbon receptor PAS-A-derived inhibitory molecule. Biochem. Pharmacol. 88:253–65.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Park EJ, et al. (2006) Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle. 5:1847–53.CrossRefPubMedGoogle Scholar
  23. 23.
    Semenza GL. (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123:3664–71.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang GL, Jiang BH, Rue EA, Semenza GL. (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. U. S. A. 92:5510–14.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Huang LE, Arany Z, Livingston DM, Bunn HF. (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J. Biol. Chem. 271:32253–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Chilov D, et al. (1999) Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1alpha. J. Cell Sci. 112:1203–12.PubMedGoogle Scholar
  27. 27.
    Zhong H, Hanrahan C, van der Poel H, Simons JW. (2001) Hypoxia-inducible factor 1alpha and 1beta proteins share common signaling pathways in human prostate cancer cells. Biochem. Biophys. Res. Commun. 284:352–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Vavilala DT, et al. (2012) Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysine demethylases. Biochem. Biophys. Res. Commun. 422:369–74.CrossRefPubMedGoogle Scholar
  29. 29.
    Mandl M, Kapeller B, Lieber R, Macfelda K. (2013) Hypoxia-inducible factor-1beta (HIF-1beta) is upregulated in a HIF-1alpha-dependent manner in 518A2 human melanoma cells under hypoxic conditions. Biochem. Biophys. Res. Commun. 434:166–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Wolff M, Jelkmann W, Dunst J, Depping R. (2013) The aryl hydrocarbon receptor nuclear translocator (ARNT/HIF-1beta) is influenced by hypoxia and hypoxia-mimetics. Cell Physiol. Biochem. 32:849–58.CrossRefPubMedGoogle Scholar
  31. 31.
    Partch CL, Gardner KH. (2011) Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proc. Natl. Acad. Sci. U. S. A. 108:7739–44.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Shi S, Yoon DY, Hodge-Bell K, Huerta-Yepez S, Hankinson O. (2010) Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth. Mol. Carcinog. 49:157–65.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Chan YY, Kalpana S, Chang WC, Chang WC, Chen BK. (2013) Expression of aryl hydrocarbon receptor nuclear translocator enhances cisplatin resistance by upregulating MDR1 expression in cancer cells. Mol. Pharmacol. 84:591–602.CrossRefPubMedGoogle Scholar
  34. 34.
    van Uden P, et al. (2011) Evolutionary conserved regulation of HIF-1beta by NF-kappaB. PLoS Genet. 7:e1001285.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Denko NC. (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer. 8:705–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Rapisarda A, Melillo G. (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat. Rev. Clin. Oncol. 9:378–90.CrossRefPubMedGoogle Scholar
  37. 37.
    Yee Koh M, Spivak-Kroizman TR, Powis G. (2008) HIF-1 regulation: not so easy come, easy go. Trends Biochem. Sci. 33:526–34.CrossRefPubMedGoogle Scholar
  38. 38.
    Legrand M, Mik EG, Johannes T, Payen D, Ince C. (2008) Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol. Med. 14:502–16.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.University of Lübeck, Center for Structural and Cell Biology in MedicineInstitute of PhysiologyLübeckGermany

Personalised recommendations