The influence of nickel and cobalt on putative members of the oxygen‐sensing pathway of erythropoietin‐producing HepG2 cells

Porwol, T.; Ehleben, Wilhelm; Zierold, Karl; Fandrey, Joachim; Acker, H.

doi:10.1046/j.1432-1327.1998.2560016.x

Cited by 54 publications

(37 citation statements)

References 40 publications

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“…As such, less ROS is generated during hypoxic incubation. This allows the full expression of particular genes that are otherwise suppressed by ROS (30,45). This model predicts that, with respect to gene regulation, inhibition of ROS production or scavenging of ROS would mimic the effects of hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Apoptosis Inhibitory Protein IAP-2 by Hypoxia

Dong

Venkatachalam

Wang

et al. 2001

Journal of Biological Chemistry

139

121

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Hypoxia is a key determinant of tissue pathology during tumor development and organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here we report the striking induction by severe hypoxia of the anti-apoptotic protein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apoptosis. IAP-2 was induced by hypoxia per se rather than by the secondary effects of hypoxia, including ATP depletion and cell injury. The inductive response did not relate to alterations of cellular redox status or arrest of mitochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nuclear run-on assays demonstrated specific increases in IAP-2 transcriptional activity after hypoxia exposure. HIF-1, the primary transcription factor that is responsible for multiple gene activation under hypoxia, does not have a role in IAP-2 expression. HIF-1 and IAP-2 were induced by different degrees of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. Moreover, cobalt chloride and desferrioxamine activated HIF-1 but not IAP-2. Finally, IAP-2 was induced by severe hypoxia in mouse embryonic stem cells that were deficient of HIF-1. Thus, this study not only provides the first demonstration of hypoxic regulation of an anti-apoptotic gene but also suggests the participation of novel hypoxia-responsive transcription mechanisms.

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Section: Discussionmentioning

confidence: 99%

Up-regulation of Apoptosis Inhibitory Protein IAP-2 by Hypoxia

Dong

Venkatachalam

Wang

et al. 2001

Journal of Biological Chemistry

139

121

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“…Cobalt is known to mimic hypoxic induction of Epo production in human hepatoma cells by competing with iron for the heme protein. 27 Although some of the 54 kb) is shorter than that in the heart and liver (1.73 kb). A larger transcript of 3.1 kb is also found in these tissues.…”

Section: Characterization Of the Fugu Epo Promotermentioning

confidence: 95%

“…Cobalt is known to mimic hypoxic induction of Epo production in human hepatoma cells by competing with iron for the heme protein. 27 Although some of the For personal use only. on March 22, 2019. by guest www.bloodjournal.org From constructs (fEpoPϪ3.8, fEpoPϪ5.9, and fEpoPϪ5.9ϩ3ЈIGR) showed 5% to 24% higher levels of expression in the presence of CoCl 2 , no marked induction of expression, as reported for the human EPO flanking sequence, was evident under various hypoxic conditions ( Figure 4D).…”

Section: Characterization Of the Fugu Epo Promotermentioning

confidence: 99%

Erythropoietin gene from a teleost fish, Fugu rubripes

Chou

Tohari

Brenner

et al. 2004

Blood

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In this paper we report the cloning and characterization of the erythropoietin (Epo) gene from the pufferfish, Fugu rubripes. This is the first nonmammalian Epo gene to be cloned. The Fugu Epo comprises 5 exons and 4 introns similar to the human EPO, and encodes a 185-amino acid protein that is 32% to 34% identical to Epo from various mammals. The synteny of genes at the Epo locus is conserved between the Fugu and humans. Unlike in mammals in which adult kidney is the primary Epo-producing organ, the heart is the main Epo-producing organ in adult Fugu. In addition to the heart, Fugu Epo is also expressed in the liver and brain similar to the human EPO. Interestingly, the transcripts in the Fugu brain are generated from a distal promoter and include an alternatively spliced first coding exon. No such brain-specific alternative splicing of Epo has been reported in mammals so far. Transient transfection studies in a fish hepatoma cell line (PLHC-1) and a human hepatoma cell line (HepG2) suggest that although the Fugu Epo promoter many not be hypoxia inducible, the gene may be regulated by hypoxia. ( IntroductionErythropoietin (Epo) is a glycoprotein hormone that plays a crucial role in ensuring supply of adequate oxygen to tissues by regulating the production of red blood cells. In mammals, Epo stimulates differentiation and proliferation of erythroid precursor cells in the bone marrow, in response to decreased environmental oxygen concentration or systemic oxygen deficiency caused by anemia. 1 In humans, fetal liver and adult kidney are the primary sites of EPO production. 1 In addition to these tissues, EPO is also produced in the central nervous system, bone marrow, spleen, heart, lung, ovary, testis, and breast cancer cells. [2][3][4][5][6][7] The production of Epo in the kidney, liver, and the central nervous system is greatly induced by hypoxic conditions. 8,9 The gene encoding the human EPO was first cloned in 1985 by 2 groups independently. 10,11 Since then, the Epo gene has been cloned from several mammalian species including nonhuman primates, rodents, ruminants, and felines. [12][13][14][15] The human EPO gene is transcribed from several start sites in the kidney and liver, and is thus independently regulated in these tissues. 16 Expression of the human EPO gene in transgenic mice has indicated that the cis-elements directing expression to the kidney are located between 6 kb and 14 kb upstream of the basal promoter, whereas the liver-specific elements are located in the 3Ј flanking region. 16 A 43-bp cis-element, capable of mediating the hypoxia response in the liver, also resides within the 3Ј flanking region, 120 bp downstream of the polyadenylation (polyA) signal. [16][17][18] Transient transfection studies in human hepatoma cell lines have demonstrated that the 3Ј enhancer induces 15-to 50-fold higher expression of a reporter gene in response to hypoxia.Although an "immunoreactive erythropoietin" that competes with human EPO for reaction with human EPO antibodies has been demonstrated in some teleos...

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“…The isolated carotid body and sinus nerve were placed in a superfusion chamber mounted on top of an opaque bench containing small holes of diameters similar to that of the carotid body. The system was mounted on the stage of a light microscope (Olympus) for light absorption measurements as described (9,10). White light from a halogen bulb (12 V, 100 W) passing through an objective (40ϫ), transilluminated the carotid body for 10 s every minute.…”

Section: Methodsmentioning

confidence: 99%

Chemoreceptor discharges and cytochrome redox changes of the rat carotid body: Role of heme ligands

Lahiri

Ehleben

Acker

1999

Proc. Natl. Acad. Sci. U.S.A.

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In superfused in vitro rat carotid body, we recorded chemoreceptor discharges and the redox state of cytochromes simultaneously to identify the primary oxygensensing protein controlling transmitter release and electrical activity of the carotid sinus nerve. These parameters were tested under the inf luence of heme ligands such as oxygen, cyanide, 4-(2-aminoethyl)-benzenesulfonyl f luoride, and CO. During stimulation, there was an initial increase in discharge frequency followed by a decline or suppression of activity. Photometric changes lagged and were maintained as nerve activity decreased. Reducing mitochondrial cytochromes by cyanide or prolonged severe hypoxia, suppressed the chemoreceptor discharge. 4-(2-Aminoethyl)-benzenesulfonyl f luoride, a specific inhibitor of the phagocytic cytochrome b 558 , also silenced the chemoreceptors after an initial excitation. CO increased the chemoreceptor discharge under normoxia, an effect inhibited by light, when the cytochromes were not reduced. When the discharges were depressed by severe hypoxia, exposure to light excited the chemoreceptors and the cytochromes were reduced. The rapidity of the chemosensory responses to light and lack of effect on dopamine release from type I cells led us to hypothesize that carotid body type I cells and the apposed nerve endings use different mechanisms for oxygen sensing: the nerve endings generate action potentials in association with membrane heme proteins whereas cytosolic heme proteins signal the redox state, releasing modulators or transmitters from type I cells.

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The influence of nickel and cobalt on putative members of the oxygen‐sensing pathway of erythropoietin‐producing HepG2 cells

Cited by 54 publications

References 40 publications

Up-regulation of Apoptosis Inhibitory Protein IAP-2 by Hypoxia

Up-regulation of Apoptosis Inhibitory Protein IAP-2 by Hypoxia

Erythropoietin gene from a teleost fish, Fugu rubripes

Chemoreceptor discharges and cytochrome redox changes of the rat carotid body: Role of heme ligands

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