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Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha.

Abstract
In response to decreased cellular oxygen concentrations the basic helix-loop-helix (bHLH)/PAS (Per, Arnt, Sim) hypoxia-inducible transcription factor, HIF-1alpha, mediates activation of networks of target genes involved in angiogenesis, erythropoiesis and glycolysis. Here we demonstrate that the mechanism of activation of HIF-1alpha is a multi-step process which includes hypoxia-dependent nuclear import and activation (derepression) of the transactivation domain, resulting in recruitment of the CREB-binding protein (CBP)/p300 coactivator. Inducible nuclear accumulation was shown to be dependent on a nuclear localization signal (NLS) within the C-terminal end of HIF-1alpha which also harbors the hypoxia-inducible transactivation domain. Nuclear import of HIF-1alpha was inhibited by either deletion or a single amino acid substitution within the NLS sequence motif and, within the context of the full-length protein, these mutations also resulted in inhibition of the transactivation activity of HIF-1alpha and recruitment of CBP. However, nuclear localization per se was not sufficient for transcriptional activation, since fusion of HIF-1alpha to the heterologous GAL4 DNA-binding domain generated a protein which showed constitutive nuclear localization but required hypoxic stimuli for function as a CBP-dependent transcription factor. Thus, hypoxia-inducible nuclear import and transactivation by recruitment of CBP can be functionally separated from one another and play critical roles in signal transduction by HIF-1alpha.
AuthorsP J Kallio, K Okamoto, S O'Brien, P Carrero, Y Makino, H Tanaka, L Poellinger
JournalThe EMBO journal (EMBO J) Vol. 17 Issue 22 Pg. 6573-86 (Nov 16 1998) ISSN: 0261-4189 [Print] England
PMID9822602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luminescent Proteins
  • Nuclear Localization Signals
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Green Fluorescent Proteins
Topics
  • Amino Acid Substitution
  • Animals
  • Biological Transport
  • COS Cells
  • Cell Hypoxia
  • Cell Nucleus (metabolism)
  • DNA-Binding Proteins (genetics, metabolism)
  • Green Fluorescent Proteins
  • Helix-Loop-Helix Motifs
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luminescent Proteins (genetics)
  • Nuclear Localization Signals (genetics)
  • Nuclear Proteins (genetics, metabolism)
  • Recombinant Fusion Proteins (genetics)
  • Signal Transduction
  • Trans-Activators (metabolism)
  • Transcription Factors
  • Transcriptional Activation

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