Regulation of erythropoietin gene expression depends on two different oxygen-sensing mechanisms

被引:14
作者
Daghman, NA [1 ]
McHale, CM
Savage, GM
Price, S
Winter, PC
Maxwell, AP
Lappin, TRJ
机构
[1] Queens Univ Belfast, Royal Victoria Hosp, Dept Haematol, Belfast BT12 6BA, Antrim, North Ireland
[2] Belfast City Hosp, Dept Nephrol, Belfast BT9 7AB, Antrim, North Ireland
关键词
erythropoietin; desferrioxamine; iron; oxygen sensing; carbon monoxide;
D O I
10.1006/mgme.1999.2851
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Erythropoietin (Epo), a glycoprotein hormone produced principally in the fetal kidney and in the adult liver in response to hypoxia, is the prime regulator of growth and differentiation in erythroid progenitor cells, The regulation of Epo gene expression is not fully understood, but two mechanisms have been proposed. One involves the participation of a heme protein capable of reversible oxygenation and the other depends on the intracellular concentration of reactive oxygen species (ROS), assumed to be a function of pO(2). We have investigated the production of Epo in response to three stimuli, hypoxia, cobalt chloride, and the iron chelator desferrioxamine, in Hep3B cells. As expected, hypoxia caused a marked rise in Epo production. When the cells were exposed to the paired stimuli of hypoxia and cobalt no further increase was found. In contrast, chelation of iron under hypoxic conditions markedly enhanced Epo production, suggesting that the two stimuli act by separate pathways, The addition of carbon monoxide inhibited hypoxia-induced Epo production, independent of desferrioxamine concentration. Taken together these data support the concept that pO(2) and ROS are sensed independently. (C) 1999 Academic Press.
引用
收藏
页码:113 / 117
页数:5
相关论文
共 19 条
[1]   EXPRESSION OF THE ERYTHROPOIETIN GENE [J].
BERU, N ;
MCDONALD, J ;
LACOMBE, C ;
GOLDWASSER, E .
MOLECULAR AND CELLULAR BIOLOGY, 1986, 6 (07) :2571-2575
[2]   Oxygen sensing and molecular adaptation to hypoxia [J].
Bunn, HF ;
Poyton, RO .
PHYSIOLOGICAL REVIEWS, 1996, 76 (03) :839-885
[3]  
Cotes PM, 1989, ERYTHROPOIETIN, P57
[4]   Cobalt and desferrioxamine reveal crucial members of the oxygen sensing pathway in HepG2 cells [J].
Ehleben, W ;
Porwol, T ;
Fandrey, J ;
Kummer, W ;
Acker, H .
KIDNEY INTERNATIONAL, 1997, 51 (02) :483-491
[5]   EFFECTS OF OXYGEN INHALATION ON ENDOGENOUS ERYTHROPOIETIN KINETICS, ERYTHROPOIESIS, AND PROPERTIES OF BLOOD-CELLS IN SICKLE-CELL-ANEMIA [J].
EMBURY, SH ;
GARCIA, JF ;
MOHANDAS, N ;
PENNATHURDAS, R ;
CLARK, MR .
NEW ENGLAND JOURNAL OF MEDICINE, 1984, 311 (05) :291-295
[6]   Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species [J].
Fandrey, J ;
Frede, S ;
Ehleben, W ;
Porwol, T ;
Acker, H ;
Jelkmann, W .
KIDNEY INTERNATIONAL, 1997, 51 (02) :492-496
[7]   ROLE OF HYDROGEN-PEROXIDE IN HYPOXIA-INDUCED ERYTHROPOIETIN PRODUCTION [J].
FANDREY, J ;
FREDE, S ;
JELKMANN, W .
BIOCHEMICAL JOURNAL, 1994, 303 :507-510
[8]   REGULATION OF ANGIOGENIC GROWTH-FACTOR EXPRESSION BY HYPOXIA, TRANSITION-METALS, AND CHELATING-AGENTS [J].
GLEADLE, JM ;
EBERT, BL ;
FIRTH, JD ;
RATCLIFFE, PJ .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 1995, 268 (06) :C1362-C1368
[9]   DIPHENYLENE IODONIUM INHIBITS THE INDUCTION OF ERYTHROPOIETIN AND OTHER MAMMALIAN GENES BY HYPOXIA - IMPLICATIONS FOR THE MECHANISM OF OXYGEN SENSING [J].
GLEADLE, JM ;
EBERT, BL ;
RATCLIFFE, PJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1995, 234 (01) :92-99
[10]   REGULATION OF THE ERYTHROPOIETIN GENE - EVIDENCE THAT THE OXYGEN SENSOR IS A HEME PROTEIN [J].
GOLDBERG, MA ;
DUNNING, SP ;
BUNN, HF .
SCIENCE, 1988, 242 (4884) :1412-1415