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

Biological Chemistry
Friederike K KosynaReinhard Depping

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-targ...Continue Reading

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Citations

Jun 10, 2017·Journal of the American Chemical Society·Rui TangVincent M Rotello
Mar 31, 2019·Molecular Cancer·Nancy T CheeShaun P Brothers
Nov 25, 2018·Cells·Friederike K Kosyna, Reinhard Depping
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May 20, 2020·Pharmaceuticals·Maha Saber-AyadEman Abu-Gharbieh
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Methods Mentioned

BETA
ubiquitination
nuclear translocation
pulldown
fluorescence microscopy
Fluorescence
Nuclear
protein assay
pull down
transfection
X-ray

Software Mentioned

AIDA Image Analyzer
BZ Analyzer
GraphPad Prism

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