Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation
Authors: L Tacchini
A Bernelli-Zazzera
G Cairo
L Bianchi
Journal: Journal of Biological Chemistry (1999)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: oxygen; iron; transferrin receptor; hypoxia; CoCl2
Affiliations: Istituto di Patologia Generale, Università di Milano e Centro di Studio sulla Patologia Cellulare, Consiglio Nazionale delle Ricerche, via Mangiagalli 31, 20133 Milano, Italy.

Abstract:  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% O(2) or treated with CoCl(2), 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 CoCl(2). 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 CoCl(2)-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-1alpha, identified by competition experiments and supershift assays, was induced in Hep3B cells by hypoxia and CoCl(2). 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. 

Retracted: No

PubPeer comments:
 ![file] , 
 ![file] , 
 #1 Thank you for this remark. It is actually possible that we inadvertently duplicated the rRNA images, as commented by Streptomyces Avellaneus, though all these rRNA bands look alike. The J Biol Chem paper is 20 years old and the experiments were performed 1-2 years earlier, before the digital images era. Therefore, unfortunately, itu2019s impossible for us to retrieve and evaluate the original images of the ethidium bromide-stained rRNA bands used for this figure. We sincerely apologize for the error, but we would like to remark that the potential use of the same image for two different blots, though inappropriate, does not affect the results and conclusions of this work, which was highly cited (279 citations in Web of Science, to date) and never criticized, so that the Transferrin Receptor is commonly included among the HIF-1 target genes. Moreover, the paper was published back to back with an independent study from a Canadian group reporting the same findings (Lok Ponka 1999 J Biol Chem. 274: 24147-24152). , 
 #3 Dr. Cairo: Thank you for your reply on this thread. Do you have any response for the other two papers identified on PubPeer? https: pubpeer.com publications 62C02E3E29E5ED6D01CFA94312B649 (2005 paper) https: pubpeer.com publications 4D0B41AA1B41E506A7D0ADB3597F4F (2004 paper) , 
 #4 Dr. Cairo, see also: https: pubpeer.com publications DB36ED46CAA4FD0E1F6C2ABD5486A7 (2009 paper) , 
 #5 Dr. Cairo, see also: https: pubpeer.com publications FBB0D110FA1B787E9B96345C63BAC1 (2006 paper) , 
 #2 Blots more similar than you would expect 4 papers. https: imgur.com JDAYv3K ,