Nuclear Translocation of Hypoxia-Inducible Factors (HIFs): Involvement of the Classical Importin alpha/beta Pathway

Biochim Biophys Acta. 2008 Mar;1783(3):394-404. doi: 10.1016/j.bbamcr.2007.12.006. Epub 2008 Jan 8.

Abstract

Hypoxia-inducible factors are the key elements in the essential process of oxygen homeostasis of vertebrate cells. Stabilisation and subsequent nuclear localisation of HIF-alpha subunits results in the activation of target genes such as vegf, epo and glut1. The passage of transcription factors e.g. HIF-1alpha into the nucleus through the nuclear pore complex is regulated by nuclear transport receptors. Therefore nucleocytoplasmic shuttling can regulate transcriptional activity by facilitating the cellular traffic of transcription factors between both compartments. Here, we report on the identification of specific interactions of hypoxia-inducible factors with nuclear transport receptors importin alpha/beta. HIF-1alpha, -1beta, and HIF-2alpha are binding to importin alpha1, alpha3, alpha5, and alpha7. The direct interaction of HIF-1alpha to alpha importins is dependent on a functional nuclear localisation signal within the C-terminal region of the protein. In contrast, the supposed N-terminal NLS is not effective. Our findings provide new insight into the mechanism of the regulation of nuclear transport of hypoxia-inducible factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Binding Sites
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Nuclear Localization Signals / chemistry
  • Nuclear Localization Signals / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Isoforms / metabolism
  • Signal Transduction
  • alpha Karyopherins / physiology*
  • beta Karyopherins / physiology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • Nuclear Localization Signals
  • Protein Isoforms
  • alpha Karyopherins
  • beta Karyopherins
  • endothelial PAS domain-containing protein 1