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J Biol Chem, Vol. 274, Issue 10, 6519-6525, March 5, 1999
From the Department of Cell and Molecular Biology, Medical Nobel
Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden
HIF-1
Regulation of the Hypoxia-inducible Transcription Factor 1
by
the Ubiquitin-Proteasome Pathway
(hypoxia-inducible factor 1) is a
basic-helix-loop-helix PAS
(Per/Arnt/Sim) transcription factor
that, under hypoxic conditions, dimerizes with a partner factor, the
basic-helix-loop-helix/PAS protein Arnt, to recognize
hypoxia-responsive elements of target genes. It has recently been
demonstrated that HIF-1 protein but not mRNA levels are
dramatically up-regulated in response to hypoxia. Here we show that
inhibitors of 26 S proteasome activity produced a dramatic accumulation
of endogenous as well as transfected HIF-1 protein under normoxic
conditions, whereas the levels of Arnt protein were not affected.
HIF-1 was polyubiquitinated in vivo under normoxic
conditions, indicating rapid degradation via the ubiquitin-proteasome
pathway. This degradation process appeared to target a region within
the C terminus of HIF-1. Importantly, HIF-1 ubiquitination was
drastically decreased under hypoxic conditions. Up-regulation of
HIF-1 protein by proteasome inhibitors did not result in
transcriptional activation of reporter genes, indicating either the
requirement of additional regulatory steps to induce functional
activity of HIF-1 or the inability of polyubiquitinated forms of
HIF-1 to mediate hypoxic signal transduction. In support of
both these notions, we demonstrate that HIF-1 showed
hypoxia-dependent translocation from the cytoplasm to the
nucleus and that this regulatory mechanism was severely impaired in the
presence of proteasome inhibitors. Taken together, these data
demonstrate that the mechanism of hypoxia-dependent
activation of HIF-1 is a complex multistep process and that
stabilization of HIF-1 protein levels is not sufficient to generate
a functional form.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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