Startseite The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways
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The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

  • Friederike K. Kosyna , Marie Nagel , Larissa Kluxen , Kim Kraushaar und Reinhard Depping EMAIL logo
Veröffentlicht/Copyright: 31. Juli 2015
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 396 Heft 12

Abstract

Hypoxia-inducible transcription factors (HIFs) regulate hundreds of genes involved in cellular adaptation to reduced oxygen availability. HIFs consist of an O2-labile α-subunit (primarily HIF-1α and HIF-2α) and a constitutive HIF-1β subunit. In normoxia the HIF-α subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1-3, resulting in recognition by von Hippel-Lindau protein, ubiquitination and proteasomal degradation. In contrast, reduced oxygen availability inhibits PHD activity resulting in HIF-1α stabilisation and nuclear accumulation. Nuclear import of HIF-1α mainly depends on classical nuclear localisation signals (NLS) and involves importin α/β heterodimers. Recently, a specific inhibitor of nuclear import has been identified that inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family. In this study we evaluated the physiological activity of this importin α/β-inhibitor (Ivermectin) in the hypoxia response pathway. Treatment with Ivermectin decreases binding activity of HIF-1α to the importin α/β-heterodimer. Moreover, HIF-1α nuclear localisation, nuclear HIF-1α protein levels, HIF-target gene expression, as well as HIF-transcriptional activity are reduced upon Ivermectin treatment. For the first time, we demonstrate the effect of specific importin α/β-inhibition on the hypoxic response on the molecular level.

Keywords: HIF; hypoxia; importin α/β; Ivermectin; nuclear transport
Corresponding author: Reinhard Depping, Institute of Physiology, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, D-23562 Lübeck, Germany, e-mail:

Acknowledgments

We thank W. Jelkmann for ongoing broad support and discussing the data. The authors are grateful to S. G. Schindler, B. Rudzewski, T. Svensson, P. Rouina and Swantje Häger for excellent technical support. The authors are grateful for the financial support by the University of Lübeck (gefördert mit den Mitteln der Sektion Medizin an der Universität zu Lübeck J19-2015). The authors declare no competing financial interests.

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Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2015-0171) offers supplementary material, available to authorized users.

Received: 2015-4-30
Accepted: 2015-7-23
Published Online: 2015-7-31
Published in Print: 2015-12-1

©2015 by De Gruyter

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  2. Reviews
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  4. What can lipidomics tell us about the pathogenesis of Alzheimer disease?
  5. Minireview
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  13. Cell Biology and Signaling
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https://doi.org/10.1515/hsz-2015-0171
Schlagwörter für diesen Artikel
HIF; hypoxia; importin α/β; Ivermectin; nuclear transport

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. The intersection between viral oncolysis, drug resistance, and autophagy
  4. What can lipidomics tell us about the pathogenesis of Alzheimer disease?
  5. Minireview
  6. The role of the Lowe syndrome protein OCRL in the endocytic pathway
  7. Research Articles/Short Communications
  8. Genes and Nucleic Acids
  9. Systematic analysis of the contribution of c-myc mRNA constituents upon cap and IRES mediated translation
  10. Protein Structure and Function
  11. The double mutation L109M and R448M of HIV-1 reverse transcriptase decreases fidelity of DNA synthesis by promoting mismatch elongation
  12. The role of Bni5 in the regulation of septin higher-order structure formation
  13. Cell Biology and Signaling
  14. Extracellular localization of catalase is associated with the transformed state of malignant cells
  15. The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways
  16. Proteolysis
  17. Inactivation of human kininogen-derived antimicrobial peptides by secreted aspartic proteases produced by the pathogenic yeast Candida albicans
  18. Corrigendum
  19. Corrigendum to: Potential importance of Maackia amurensis agglutinin in non-small cell lung cancer
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