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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-07-2140.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3690-3698
RED CELLS
Relationships and distinctions in iron-regulatory networks
responding to interrelated signals
Martina Muckenthaler,
Alexandra Richter,
Niki Gunkel,
Dieter Riedel,
Maria Polycarpou-Schwarz,
Sabine Hentze,
Mechthild Falkenhahn,
Wolfgang Stremmel,
Wilhelm Ansorge, and
Matthias W. Hentze
From the European Molecular Biology Laboratory,
Heidelberg; Intervet International, Schwabenheim; Department of
Medicine, University of Heidelberg; and the Department of Biocomputing,
Krebsforschungszentrum, Heidelberg, Germany.
Specialized cDNA-based microarrays (IronChips) were
developed to investigate complex physiological gene-regulatory
patterns in iron metabolism. Approximately 115 human cDNAs
were strategically selected to represent genes involved either in iron
metabolism or in interlinked pathways (eg, oxidative stress, nitric
oxide [NO] metabolism, or copper metabolism), and were
immobilized on glass slides. HeLa cells were treated with iron
donors or iron chelators, or were subjected to oxidative stress
(H2O2) or NO (sodium nitroprusside). In
addition, we generated a stable transgenic HeLa cell line expressing
the HFE gene under an inducible promoter. Gene-response
patterns were recorded for all of these interrelated experimental
stimuli, and analyzed for common and distinct responses that define
signal-specific regulatory patterns. The resulting regulatory
patterns reveal and define degrees of relationship between distinct
signals. Remarkably, the gene responses elicited by the altered
expression of the hemochromatosis protein HFE and by pharmacological
iron chelation exhibit the highest degree of relatedness, both for
iron-regulatory protein (IRP) and non-IRP target genes. This
finding suggests that HFE expression directly affects the
intracellular chelatable iron pool in the transgenic cell
line. Furthermore, cells treated with the iron donors hemin or ferric
ammonium citrate display response patterns that permit the
identification of the iron-loaded state in both cases, and the
discrimination between the sources of iron loading. These findings also
demonstrate the broad utility of gene-expression profiling with the
IronChip to study iron metabolism and related human diseases.
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