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Science 9 December 1988:
Vol. 242. no. 4884, pp. 1412 - 1415
DOI: 10.1126/science.2849206
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Articles

Science, Vol 242, Issue 4884, 1412-1415
Copyright © 1988 by American Association for the Advancement of Science

articles

Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein

MA Goldberg, SP Dunning, and HF Bunn

Howard Hughes Medical Institute, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.

Erythropoietin (Epo), the hormone that stimulates red blood cell production, is synthesized in the kidney and liver in response to hypoxia. The human hepatoma cell line Hep3B regulates its production of Epo in a physiologic manner. Either hypoxia or cobalt chloride markedly increases expression of Epo mRNA as well as production of biologically active and immunologically distinct Epo protein. New protein synthesis is required before the induction of increased levels of hypoxia- or cobalt-induced Epo mRNA. Hypoxia, cobalt chloride, and nickel chloride appear to stimulate Epo production through a common pathway. The inhibition of Epo production at low partial pressures of oxygen by carbon monoxide provides evidence that a heme protein is integrally involved in the oxygen-sensing mechanism. This hypothesis is further supported by the finding that when heme synthesis is blocked, hypoxia-, cobalt-, and nickel-induced Epo production are all markedly inhibited. A model is proposed in which a ligand-dependent conformational change in a heme protein accounts for the mechanism by which hypoxia as well as cobalt and nickel stimulate the production of Epo.


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Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications.
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N. S. Chandel and P. T. Schumacker (2000)
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F van Breukelen, R Maier, and S. Hand (2000)
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R. Wenger (2000)
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Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors.
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Hypoxia-Inducible Factor-1alpha Mediates Hypoxia-Induced Delayed Neuronal Death That Involves p53.
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J. Neurosci. 19, 6818-6824
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E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats.
N. Hanasato, M. Oka, M. Muramatsu, M. Nishino, H. Adachi, and Y. Fukuchi (1999)
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Pigment Epithelium-Derived Factor: A Potent Inhibitor of Angiogenesis.
D. W. Dawson, O. V. Volpert, P. Gillis, S. E. Crawford, H. Xu, W. Benedict, and N. P. Bouck (1999)
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T. Kietzmann, K. I. Hirsch-Ernst, G. F. Kahl, and K. Jungermann (1999)
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R. Bertini, O.M. Zack Howard, H.-F. Dong, J. J. Oppenheim, C. Bizzarri, R. Sergi, G. Caselli, S. Pagliei, B. Romines, J. A. Wilshire, et al. (1999)
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A. Behrooz and F. Ismail-Beigi (1999)
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Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes.
K. E. Kwast, P. V. Burke, B. T. Staahl, and R. O. Poyton (1999)
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   Abstract »    Full Text »    PDF »
Hypoxia Alters Iron-regulatory Protein-1 Binding Capacity and Modulates Cellular Iron Homeostasis in Human Hepatoma and Erythroleukemia Cells.
I. Toth, L. Yuan, J. T. Rogers, H. Boyce, and K. R. Bridges (1999)
J. Biol. Chem. 274, 4467-4473
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Protective Function of von Hippel-Lindau Protein against Impaired Protein Processing in Renal Carcinoma Cells.
M. Gorospe, J. M. Egan, B. Zbar, M. Lerman, L. Geil, I. Kuzmin, and N. J. Holbrook (1999)
Mol. Cell. Biol. 19, 1289-1300
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Effects of Pro- and Antioxidative Compounds on Renal Production of Erythropoietin.
I. Neumcke, B. Schneider, J. Fandrey, and H. Pagel (1999)
Endocrinology 140, 641-645
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