TY - JOUR
T1 - Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation
AU - Tacchini, Lorenza
AU - Bianchi, Laura
AU - Bernelli-Zazzera, Aldo
AU - Cairo, Gaetano
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1999/8/20
Y1 - 1999/8/20
N2 - The tight relationship between oxygen and iron prompted us to investigate whether the expression of transferrin receptor (TfR), which mediates cellular iron uptake, is regulated by hypoxia. In Hep3B human hepatoma cells incubated in 1% O2 or treated with CoCl2, which mimics hypoxia, we detected a 3-fold increase of TfR mRNA despite a decrease of iron regulatory proteins activity. Increased expression resulted from a 4-fold stimulation of the nuclear transcription rate of the TfR gene by both hypoxia and CoCl2. A role for hypoxia-inducible factor (HIF-1), which activates transcription by binding to hypoxia-responsive elements in the activation of TfR, stems from the following observations. (a) Hypoxia and CoCl2-dependent expression of luciferase reporter gene in transiently transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative hypoxia-responsive element sequence, (b) mutation of this sequence prevented hypoxic stimulation of luciferase activity, (c) binding to this sequence of HIF-1α, identified by competition experiments and supershift assays, was induced in Hep3B cells by hypoxia and CoCl2. In erythroid K562 cells, the same treatments did not affect iron regulatory proteins activity, thus resulting in a stimulation of TfR gene expression higher than in hepatoma cells.
AB - The tight relationship between oxygen and iron prompted us to investigate whether the expression of transferrin receptor (TfR), which mediates cellular iron uptake, is regulated by hypoxia. In Hep3B human hepatoma cells incubated in 1% O2 or treated with CoCl2, which mimics hypoxia, we detected a 3-fold increase of TfR mRNA despite a decrease of iron regulatory proteins activity. Increased expression resulted from a 4-fold stimulation of the nuclear transcription rate of the TfR gene by both hypoxia and CoCl2. A role for hypoxia-inducible factor (HIF-1), which activates transcription by binding to hypoxia-responsive elements in the activation of TfR, stems from the following observations. (a) Hypoxia and CoCl2-dependent expression of luciferase reporter gene in transiently transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative hypoxia-responsive element sequence, (b) mutation of this sequence prevented hypoxic stimulation of luciferase activity, (c) binding to this sequence of HIF-1α, identified by competition experiments and supershift assays, was induced in Hep3B cells by hypoxia and CoCl2. In erythroid K562 cells, the same treatments did not affect iron regulatory proteins activity, thus resulting in a stimulation of TfR gene expression higher than in hepatoma cells.
UR - http://www.scopus.com/inward/record.url?scp=0033588021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033588021&partnerID=8YFLogxK
U2 - 10.1074/jbc.274.34.24142
DO - 10.1074/jbc.274.34.24142
M3 - Article
C2 - 10446187
AN - SCOPUS:0033588021
VL - 274
SP - 24142
EP - 24146
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 34
ER -