The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1-Lalpha.

The formation of disulfide bonds in the endoplasmic reticulum requires protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin 1 (ERO1) that reoxidizes PDI. We report here that the expression of the rat, mouse and human homologues of ERO1-Like protein alpha but not of the isoform ERO1-Lbeta are stimulated by hypoxia in rats vivo and in rat, mouse and human cell cultures. The temporal pattern of hypoxic ERO1-Lalpha induction is very similar to that of genes triggered by the hypoxia inducible transcription factor (HIF-1) and is characteristically mimicked by cobalt and by deferoxamine, but is absent in cells with a defective aryl hydrocarbon receptor translocator (ARNT, HIF-1beta). We speculate from these findings that the expression of ERO1-Lalpha is probably regulated via the HIF-pathway and thus belongs to the family of classic oxygen regulated genes. Activation of the unfolded protein response (UPR) by tunicamycin, on the other hand, strongly induced ERO1-Lbeta and more moderately ERO1-Lalpha expression. The expression of the two ERO1-L isoforms therefore appears to be differently regulated, in the way that ERO1-Lalpha expression is mainly controlled by the cellular oxygen tension, whilst ERO1-Lbeta is triggered mainly by UPR. The physiological meaning of the oxygen regulation of ERO1-Lalpha expression likely is to maintain the transfer rate of oxidizing equivalents to PDI in situations of an altered cellular redox state induced by changes of the cellular oxygen tension.

[1]  N. Sonenberg,et al.  Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α , 2002, Molecular and Cellular Biology.

[2]  R. Sitia,et al.  Formation, isomerisation and reduction of disulphide bonds during protein quality control in the endoplasmic reticulum , 2002, Histochemistry and Cell Biology.

[3]  L. Hendershot,et al.  The Unfolding Tale of the Unfolded Protein Response , 2001, Cell.

[4]  K. Kangawa,et al.  Adrenomedullin (11–26): a novel endogenous hypertensive peptide isolated from bovine adrenal medulla , 2001, Peptides.

[5]  S. McKnight,et al.  A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF , 2001, Science.

[6]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[7]  Amy S. Lee,et al.  The glucose-regulated proteins: stress induction and clinical applications. , 2001, Trends in biochemical sciences.

[8]  A. Sickmann,et al.  Identification of post‐translationally modified proteins in proteome studies , 2001, Electrophoresis.

[9]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[10]  J. Weissman,et al.  Biochemical basis of oxidative protein folding in the endoplasmic reticulum. , 2000, Science.

[11]  I. Braakman,et al.  The CXXCXXC motif determines the folding, structure and stability of human Ero1‐Lα , 2000, The EMBO journal.

[12]  N. Bulleid,et al.  Endoplasmic Reticulum Oxidoreductin 1-Lβ (ERO1-Lβ), a Human Gene Induced in the Course of the Unfolded Protein Response* 210 , 2000, The Journal of Biological Chemistry.

[13]  S. Takahashi,et al.  Hypoxic Induction of Prolyl 4-Hydroxylase α(I) in Cultured Cells* , 2000, The Journal of Biological Chemistry.

[14]  S. Tanaka,et al.  Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death* , 2000, The Journal of Biological Chemistry.

[15]  M. Rocchi,et al.  ERO1-L, a Human Protein That Favors Disulfide Bond Formation in the Endoplasmic Reticulum* , 2000, The Journal of Biological Chemistry.

[16]  A. Kurtz,et al.  Tissue hypoxygenation activates the adrenomedullin system in vivo. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[17]  C. Kaiser,et al.  Ero1p oxidizes protein disulfide isomerase in a pathway for disulfide bond formation in the endoplasmic reticulum. , 1999, Molecular cell.

[18]  W. Claycomb,et al.  Adrenomedullin Gene Expression Is Developmentally Regulated and Induced by Hypoxia in Rat Ventricular Cardiac Myocytes* , 1998, The Journal of Biological Chemistry.

[19]  L. Ruddock,et al.  Protein folding: A missing redox link in the endoplasmic reticulum , 1998, Current Biology.

[20]  G. Semenza,et al.  Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α , 1997, The Journal of Biological Chemistry.

[21]  Y. Fujii‐Kuriyama,et al.  A point mutation responsible for defective function of the aryl-hydrocarbon-receptor nuclear translocator in mutant Hepa-1c1c7 cells. , 1997, European journal of biochemistry.

[22]  M. Gassmann,et al.  Oxygen- and dioxin-regulated gene expression in mouse hepatoma cells. , 1997, Kidney international.

[23]  G. Semenza,et al.  Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1. , 1995, Biochemical and biophysical research communications.

[24]  G. Semenza,et al.  Purification and Characterization of Hypoxia-inducible Factor 1 (*) , 1995, The Journal of Biological Chemistry.

[25]  D. Ruiter,et al.  Covalent dimerization of vascular permeability factor/vascular endothelial growth factor is essential for its biological activity. Evidence from Cys to Ser mutations. , 1994, The Journal of biological chemistry.

[26]  K. Kivirikko,et al.  Cloning, baculovirus expression, and characterization of the alpha subunit of prolyl 4-hydroxylase from the nematode Caenorhabditis elegans. This alpha subunit forms an active alpha beta dimer with the human protein disulfide isomerase/beta subunit. , 1994, The Journal of biological chemistry.

[27]  C. Kane,et al.  Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promoter viral oncogene fusion construct. , 1990, The Journal of biological chemistry.

[28]  R. Sutherland,et al.  Enhanced synthesis of stress proteins caused by hypoxia and relation to altered cell growth and metabolism. , 1990, British Journal of Cancer.

[29]  H. Gross,et al.  The expression of the TMV-specific 30-kDa protein in tobacco protoplasts is strongly and selectively enhanced by actinomycin. , 1989, Virology.

[30]  L. Poellinger,et al.  DNA binding properties of dioxin receptors in wild-type and mutant mouse hepatoma cells. , 1988, Biochemistry.

[31]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[32]  J. Jacob.  Changes in nucleolar ultrastructure during amphibian development. , 1969, Experimental cell research.

[33]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[34]  C. Kaiser,et al.  The ERO1 gene of yeast is required for oxidation of protein dithiols in the endoplasmic reticulum. , 1998, Molecular cell.

[35]  J. Weissman,et al.  Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum. , 1998, Molecular cell.

[36]  C. Mantel,et al.  Biochemical properties of human urinary megakaryocyte colony-stimulating factor and erythropoietin: the role of sulfhydryl groups and disulfide bonds. , 1986, Experimental cell biology.