Nucleic Acids Research, Vol 27, Issue 21 4223-4227, Copyright © 1999 by Oxford University Press
L Bianchi, L Tacchini and G Cairo
Treatment with iron chelators mimics hypoxic induction of the hypoxia
inducible factor (HIF-1) which activates transcription by binding to
hypoxia responsive elements (HRE). We investigated whether HIF-1 is
involved in transcriptional activation of the transferrin receptor (TfR), a
membrane protein which mediates cellular iron uptake, in response to iron
deprivation. The transcription rate of the TfR gene in isolated nuclei was
up-regulated by treatment of Hep3B human hepatoma cells with the iron
chelator desferrioxamine (DFO). The role of HIF-1 in the activation of TfR
was indicated by the following observations: (i) DFO-dependent activation
of a luciferase reporter gene in transfected Hep3B cells was mediated by a
fragment of the human TfR promoter containing a putative HRE sequence; (ii)
mutation of this sequence prevented stimulation of luciferase activity;
(iii) binding to this sequence of HIF-1alpha, identified by competition
experiments and supershift assays, was induced by DFO. Furthermore, in
mouse hepatoma cells unable to assemble functional HIF-1, inducibility of
TfR transcription by DFO was lost and TfR mRNA up-regulation was reduced.
These results, which show the role of HIF-1 in the control of TfR gene
expression in conditions of iron depletion, give insights into the
mechanisms of transcriptional regulation which concur with the well-
characterized post-transcriptional control of TfR expression to expand the
extent of response to iron deficiency.
ARTICLES
HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation
Istituto di Patologia Generale and Istituto Scienze Mediche, IRCCS Ospedale Maggiore, Universita di Milano, Italy.
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