Cell-surface events for metallothionein-1 and heme oxygenase-1 regulation by the hemopexin-heme transport system.
A model has been developed for the hemopexin receptor-mediated heme transport system based on iron uptake in yeast. Two steps are required: reduction followed by oxidation by a multi-copper-oxidase. Furthermore, in the hemopexin system, the surface redox events have been linked with gene regulation. The impermeable Cu(I) chelator bathocuproinedisulfonate (BCDS) is shown here to abrogate heme oxygenase-1 (HO-1) mRNA induction by heme-hemopexin. A role for Cu(I) in the regulation of HO-1 and MT-1 (Sung et al., 1999) by hemopexin supports the participation of electron transport processes at the cell surface as does competition by the reductase activator, ferric citrate, which inhibits the induction of MT-1 and HO-1 mRNA by heme-hemopexin. There is a key role for the hemopexin receptor because neither ferric citrate nor iron-transferrin alone regulates MT-1 or HO-1. Cell-surface copper is the first molecule to link the concomitant regulation of HO-1 and MT-1 by the hemopexin receptor. In addition, cytochrome b5 and cytochrome b5 reductase are implicated here in the response of cells to heme-hemopexin. Reduction of one or more electron donors of the reductase and oxidation of the electron acceptor, b5 heme, leads to gene regulation, but only when heme-hemopexin is bound to its receptor. Protein kinase cascades, including JNK, are activated by the hemopexin receptor itself upon ligand binding but are modulated by a Cu(I)-dependent process likely to be heme uptake.
Sung
L
L
Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110-2499, USA.
Shibata
M
M
Eskew
J D
JD
Shipulina
N
N
Morales
P J
PJ
Smith
A
A
D000818:Animals; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006466:Hemopexin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D011441:Propylthiouracil / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018000:Receptors, Peptide / Q000378:metabolism; D015398:Signal Transduction; D014168:Transferrin / Q000494:pharmacology
D002614:Chelating Agents; D005290:Ferric Compounds; D008565:Membrane Proteins; D010618:Phenanthrolines; D012333:RNA, Messenger; D018000:Receptors, Peptide; D014168:Transferrin; C028283:diferric transferrin; C047453:hemopexin receptor; D006418:Heme; C025314:ferric citrate; D011441:Propylthiouracil; C028559:bathocuproine sulfonate; D006466:Hemopexin; D008668:Metallothionein; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases