Regulation of the Erythropoietin Gene: Evidence That the Oxygen Sensor Is a Heme Protein

American Association for the Advancement of Science (AAAS) - Tập 242 Số 4884 - Trang 1412-1415 - 1988
Mark A. Goldberg1, Susan P. Dunning1, H. Franklin Bunn1
1Howard Hughes Medical Institute, Division of Hematology, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115.

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

BERK, L, ERYTHROPOIETIC EFFECT OF COBALT IN PATIENTS WITH OR WITHOUT ANEMIA, NEW ENGLAND JOURNAL OF MEDICINE 240: 754 (1949).

BUNN H.F. HEMOGLOBIN MOL GENET (1986).

CAUGHEY, W.S., CARBON MONOXIDE BONDING IN HEMEPROTEINS, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 174: 148 (1970).

COBURN, R.F., MECHANISMS OF CARBON-MONOXIDE TOXICITY, PREVENTIVE MEDICINE 8: 310 (1979).

DEMATTEIS, F, INHIBITION OF HEME SYNTHESIS CAUSED BY COBALT IN RAT-LIVER - EVIDENCE FOR 2 DIFFERENT SITES OF ACTION, BIOCHEMICAL JOURNAL 162: 213 (1977).

FISHER, J.W., EFFECTS OF TESTOSTERONE COBALT AND HYPOXIA ON ERYTHROPOIETIN PRODUCTION IN ISOLATED PERFUSED DOG KIDNEY, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 149: 75 (1968).

FRIED, W, ERYTHROPOIETIC EFFECT OF PLASMA FROM MICE RECEIVING TESTOSTERONE, NATURE 206: 1160 (1965).

GOLDBERG, M.A., THE REGULATED EXPRESSION OF ERYTHROPOIETIN BY 2 HUMAN HEPATOMA-CELL LINES, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 84: 7972 (1987).

GOLDBERG M.A. unpublished data.

GOLDWASSER, E, STUDIES ON ERYTHROPOIESIS .5. THE EFFECT OF COBALT ON THE PRODUCTION OF ERYTHROPOIETIN, BLOOD 13: 55 (1958).

GROSS, D.M., ENHANCED ERYTHROPOIETIN AND PROSTAGLANDIN-E PRODUCTION IN DOG FOLLOWING RENAL-ARTERY CONSTRICTION, PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 151: 498 (1976).

HAGIWARA, M, ROLE OF ENDOGENOUS PROSTAGLANDIN-E-2 IN ERYTHROPOIETIN PRODUCTION AND DOME FORMATION BY HUMAN RENAL-CARCINOMA CELLS IN CULTURE, JOURNAL OF CLINICAL INVESTIGATION 74: 1252 (1984).

HOFFMAN, B.M., MANGANESE-SUBSTITUTED HEMOGLOBIN AND MYOGLOBIN, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 244: 174 (1975).

IGARASHI, J, EFFECTS OF ADMINISTRATION OF COBALT CHLORIDE AND COBALT PROTOPORPHYRIN ON DELTA-AMINOLEVULINATE SYNTHASE IN RAT-LIVER, JOURNAL OF BIOCHEMISTRY 84: 997 (1978).

JACOBSON, L.O., ROLE OF THE KIDNEY IN ERYTHROPOIESIS, NATURE 179: 633 (1957).

JASMIN, G, POLYCYTHEMIA INDUCED IN RATS BY INTRARENAL INJECTION OF NICKEL SULFIDE NI3S2, PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 148: 774 (1975).

JELKMANN, W, RENAL ERYTHROPOIETIN - PROPERTIES AND PRODUCTION, REVIEWS OF PHYSIOLOGY BIOCHEMISTRY AND PHARMACOLOGY 104: 139 (1986).

KURTZ, A, ROLE OF PROSTAGLANDINS IN HYPOXIA-STIMULATED ERYTHROPOIETIN PRODUCTION, AMERICAN JOURNAL OF PHYSIOLOGY 249: C3 (1985).

KURTZ, A, ERYTHROPOIETIN PRODUCTION BY FETAL MOUSE-LIVER CELLS IN RESPONSE TO HYPOXIA AND ADENYLATE-CYCLASE STIMULATION, ENDOCRINOLOGY 118: 567 (1986).

Kurtz, A., Proceedings of the National Academy of Sciences of the United States of America 80: 4008 (1983).

MORSE, E.E., DOSE-RESPONSE AND TIME-RESPONSE STUDY OF ERYTHROCYTOSIS IN RATS AFTER INTRARENAL INJECTION OF NICKEL SUBSULFIDE, ANNALS OF CLINICAL AND LABORATORY SCIENCE 7: 17 (1977).

NECAS, E, UNRESPONSIVENESS OF ERYTHROPOIETIN-PRODUCING CELLS TO CYANIDE, AMERICAN JOURNAL OF PHYSIOLOGY 222: 1187 (1972).

PERUTZ, M.F., STEREOCHEMISTRY OF COOPERATIVE EFFECTS IN HAEMOGLOBIN, NATURE 228: 726 (1970).

ROGERS, G.M., AM J MED 58: 31 (1975).

SCHOENFELD, N, THE EFFECTS OF SUCCINYLACETONE (4,6-DIOXOHEPTANOIC ACID) ON DELTA-AMINOLEVULINATE SYNTHASE ACTIVITY AND THE CONTENT OF HEME IN MONOLAYERS OF CHICK-EMBRYO LIVER-CELLS, BIOCHIMICA ET BIOPHYSICA ACTA 721: 408 (1982).

SCHOOLEY, J.C., STIMULATION OF ERYTHROPOIESIS IN PLETHORIC MOUSE BY CYCLIC-AMP AND ITS INHIBITION BY ANTIERYTHROPOIETIN, PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 137: 1289 (1971).

SHEDLOFSKY, S.I., HEME-SYNTHESIS FROM EXOGENOUS 5-AMINOLEVULINATE IN CULTURED CHICK-EMBRYO HEPATOCYTES - EFFECTS OF INDUCERS OF CYTOCHROMES-P-450, BIOCHEMICAL JOURNAL 248: 229 (1987).

SHERWOOD, J.B., STIMULATION BY CAMP OF ERYTHROPOIETIN SECRETION BY AN ESTABLISHED HUMAN RENAL-CARCINOMA CELL-LINE, BLOOD 69: 1053 (1987).

SHIBAYAMA, N, OXYGEN EQUILIBRIUM STUDY AND LIGHT-ABSORPTION SPECTRA OF NI(II)-FE(II) HYBRID HEMOGLOBINS, JOURNAL OF MOLECULAR BIOLOGY 192: 323 (1986).

SINCLAIR, P, FORMATION OF COBALT PROTOPORPHYRIN IN THE LIVER OF RATS - MECHANISM FOR THE INHIBITION OF LIVER HEME-BIOSYNTHESIS BY INORGANIC COBALT, BIOCHEMICAL JOURNAL 178: 529 (1979).

SINCLAIR, P.R., FORMATION OF COBALT PROTOPORPHYRIN BY CHICKEN HEPATOCYTES IN CULTURE - RELATIONSHIP TO DECREASE OF 5-AMINOLAEVULINATE SYNTHASE CAUSED BY COBALT, BIOCHEMICAL PHARMACOLOGY 31: 993 (1982).

TSCHUDY, D.P., INHIBITION OF DELTA-AMINOLEVULINIC-ACID DEHYDRASE BY 4,6-DIOXOHEPTANOIC ACID, JOURNAL OF BIOLOGICAL CHEMISTRY 256: 9915 (1981).

UENO, M, EFFECTS OF REACTIVE OXYGEN METABOLITES ON ERYTHROPOIETIN PRODUCTION IN RENAL-CARCINOMA CELLS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 154: 773 (1988).

WATERMAN, M.R., STUDIES ON MODIFIED HEMOGLOBINS .1. PROPERTIES OF HYBRID HEMOGLOBINS CONTAINING MANGANESE PROTOPORPHYRIN-IX, JOURNAL OF BIOLOGICAL CHEMISTRY 245: 5847 (1970).

YASTREBOV, A.P., MECHANISM OF COBALT ACTION ON ERYTHROPOIESIS, FEDERATION PROCEEDINGS 25: T630 (1966).

YONETANI, T, STUDIES ON CYTOCHROME C PEROXIDASE .15. COMPARISON OF MANGANESE PORPHYRIN-CONTAINING CYTOCHROME C PEROXIDASE, HORSERADISH PEROXIDASE, AND MYOGLOBIN, JOURNAL OF BIOLOGICAL CHEMISTRY 244: 4580 (1969).

YONETANI, T, STUDIES ON COBALT MYOGLOBINS AND HEMOGLOBINS .1. PREPARATION AND OPTICAL-PROPERTIES OF MYOGLOBINS AND HEMOGLOBINS CONTAINING COBALT PROTO-PORPHYRINS, MESO-PORPHYRINS, AND DEUTEROPORPHYRINS AND THERMODYNAMIC CHARACTERIZATION OF THEIR REVERSIBLE OXYGENATION, JOURNAL OF BIOLOGICAL CHEMISTRY 249: 682 (1974).

ZANJANI, E.D., LIVER AS PRIMARY SITE OF ERYTHROPOIETIN FORMATION IN FETUS, JOURNAL OF LABORATORY AND CLINICAL MEDICINE 89: 640 (1977).

Thông tin
Thông tin xuất bản

American Association for the Advancement of Science (AAAS)

Tập 242 Số 4884

1412-1415

Thông tin tác giả