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J. Biol. Chem., Vol. 275, Issue 28, 21048-21054, July 14, 2000
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From the Department of Cell Biology, The Lerner Research Institute,
Cleveland Clinic Foundation, Cleveland, Ohio 44195
A role of the copper protein ceruloplasmin (Cp)
in iron metabolism is suggested by its ferroxidase activity and by the
tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle
cell disease, pregnancy, and inflammation. However, little is known
about the cellular and molecular mechanism(s) involved. We have
reported that iron chelators increase Cp mRNA expression and
protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we
have shown that the increase in Cp mRNA is due to increased rate of
transcription. We here report the results of new studies designed to
elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the
Cp gene was cloned from a human genomic library. A
4774-base pair segment of the Cp promoter/enhancer driving
a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron
deficiency or hypoxia increased luciferase activity by 5-10-fold
compared with untreated cells. Examination of the sequence showed three
pairs of consensus hypoxia-responsive elements (HREs). Deletion and
mutation analysis showed that a single HRE was necessary and sufficient
for gene activation. The involvement of hypoxia-inducible factor-1
(HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1
Role of Hypoxia-inducible Factor-1 in Transcriptional Activation
of Ceruloplasmin by Iron Deficiency*
and HIF-1
binding to a radiolabeled oligonucleotide
containing the Cp promoter HRE. Furthermore, iron
deficiency (and hypoxia) did not activate Cp gene
expression in Hepa c4 hepatoma cells deficient in HIF-1, as shown
functionally by the inactivity of a transfected Cp
promoter-luciferase construct and by the failure of HIF-1 to bind the
Cp HRE in nuclear extracts from these cells. These results
are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to
understand these observations.
*
This work was supported by National Institutes of Health
Grant HL29582 (to P. L. F.) and by a Fellowship of the American Heart Association of Northeast Ohio (to C. K. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Cell Biology,
The Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid
Ave., Cleveland, OH 44195. Tel.: 216-444-8053; Fax: 216-444-9404;
E-mail: foxp@ccf.org.
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