Hepatic Regeneration and Erythropoietin Production in the Rat

Naughton, Brian A.; Kaplan, Stephen M.; Roy, Marie‐Josée; Burdowski, Allen J.; Gordon, Albert S.; Piliero, Sam J.

doi:10.1126/science.847471

Cited by 73 publications

(36 citation statements)

References 15 publications

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“…Because the timing of the switch relative to birth is very different in different mammals, it is clear that it is not primarily determined by the alterations that occur in the circulation and oxygenation at the time of birth. A potentially relevant observation is that the ability to produce substantial amounts of EPO is greatly increased in regenerating liver after partial hepatectomy or in the recovery phase of viral hepatitis (84,85).…”

Section: Epo Productionmentioning

confidence: 99%

Hif-1

Maxwell

2003

Journal of the American Society of Nephrology

117

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Section: Epo Productionmentioning

confidence: 99%

Hif-1

Maxwell

2003

Journal of the American Society of Nephrology

117

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“…Co-expression of the TR2 Orphan Receptor and EPO in Fetal Mouse Liver, Kidney, and Brain-The kidney and the liver are the major organs known to produce EPO in mammals (29,47,48). Within the mammalian embryo, EPO is produced primarily by the fetal liver during midgestation, and by the kidney from late gestation to adulthood.…”

Section: Figmentioning

confidence: 99%

Suppression of the Human Erythropoietin Gene Expression by the TR2 Orphan Receptor, a Member of the Steroid Receptor Superfamily

Lee¹,

Young

Shih³

et al. 1996

Journal of Biological Chemistry

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A DNA response element, TR2RE-EPO (5-TCTGAC-CTCTCGACCTAC-3) has been identified in the 3-minimal hypoxia-inducible enhancer of the human erythropoietin gene for the TR2 orphan receptor, an androgenrepressed transcription factor and a member of the steroid/thyroid hormone receptor superfamily. Electrophoretic mobility shift assay showed a specific binding with high affinity (K d ‫؍‬ 0.14 nM) between the TR2 orphan receptor and the TR2RE-EPO. Our data further indicated that this specific binding is not due to the homo-dimerization of the TR2 orphan receptor. In addition, reporter gene expression using chloramphenicol acetyltransferase assay demonstrated that the TR2 orphan receptor may suppress the expression of the chloramphenicol acetyltransferase activities via the TR2RE-EPO in the hypoxic/normoxic human hepatoma HepG2 cells. Finally, our in situ hybridization data also indicated that the TR2 orphan receptor and the erythropoietin transcripts can be co-expressed in mouse kidney and liver. Together, our data suggest that the human erythropoietin gene could represent the first human target gene regulated directly by the human TR2 orphan receptor.Members of the steroid/thyroid hormone receptor superfamily are transcriptional factors that regulate the expression of target genes by binding to specific cis-acting sequences in the nuclei of animal cells (1). These nuclear receptors include receptors for steroid, thyroid, vitamin D 3 , vitamin A-derived hormones, and a large number of orphan receptors in which cognate ligands have not yet been identified (2, 3). Numerous orphan receptors have been identified by low stringency hybridization screening and other cloning techniques (4, 5) (reviewed in Refs. 6 and 7). Thus, they share common modular architecture within the superfamily, including a variable Nterminal portion, a high degree of homology in the DNA-binding domain with two zinc fingers, and a putative ligand-binding domain at the C-terminal region. Consequently, physiological roles of orphan receptors have been postulated and subjected to speculation since they were initially identified. More recent efforts exploring their potential functions have demonstrated the remarkable impact of the nuclear receptor superfamily. Novel ligands or activators for several orphan receptors have been identified, for instance, 9-cis-retinoic acid, 15-deoxy-⌬ 12,14 -prostaglandin J 2 , and melatonin (5-methyoxy-N-acetyltryptamine) for retinoid X receptor (RXR), 1 peroxisome proliferator-activated receptor ␥, and retinoid Z receptors ␣ and ␤ (8 -11). In addition, some orphan receptors are constitutive transactivators or repressors, such as the TR3 orphan receptor or COUP-TF I (12-17). Certain orphan receptors and classical steroid receptors can be activated to regulate gene transcription by modulators, such as neurotransmitters (dopamine), or by internal changes in phosphorylation pathways (6). Several orphan receptors, however, may function as co-regulators of ligand-dependent receptors to modulate ligand-mediated signaling pathwa...

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“…In hypoxic animals, EP can be extracted from renal tissues but not other tissues (2, 3). The only other organ which has been implicated in EP production is the liver of fetal (14) or nephrectomized (1,3,8) animals. The recent cloning of the mouse EP gene (12) provides the probes necessary for analysis of the organ distribution, quantitation, and time course of accumulation of EP-specific mRNA transcripts in mice made hypoxic by blood loss.…”

mentioning

confidence: 99%

Anemia induces accumulation of erythropoietin mRNA in the kidney and liver.

Bondurant¹,

Koury²

1986

Mol. Cell. Biol.

222

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Regulation of the production of erythropoietin occurs in the kidney and liver largely through control of accumulation of erythropoietin mRNA. Erythropoietin mRNA was first detected in kidneys at 1.5 h postanemia and reached a plateau value at least 200-fold above the control value by 4 to 8 h. A 20-base sequence immediately upstream from the reported erythropoietin mRNA initiation site is complementary to a hypervariable sequence in 18S rRNA.Erythropoietin (EP) is a glycoprotein hormone which is the principal regulator of mammalian erythrocyte development. Studies measuring the biological activity of EP have demonstrated that the kidney plays a predominant role in raising circulating EP titers in response to hypoxia (6, 7). In hypoxic animals, EP can be extracted from renal tissues but not other tissues (2, 3). The only other organ which has been implicated in EP production is the liver of fetal (14) or nephrectomized (1,3,8) animals. The recent cloning of the mouse EP gene (12) provides the probes necessary for analysis of the organ distribution, quantitation, and time course of accumulation of EP-specific mRNA transcripts in mice made hypoxic by blood loss.RNA was isolated from mouse organs by homogenizing them in guanidine isothiocyanate and sedimenting the RNA through 5.7 M CsCl (4). Polyadenylated RNA was isolated by chromatography with oligo(dT)-cellulose. For electrophoresis, 6 to 25 ,ug of polyadenylated RNA or 30 to 50 ,ug of total cellular RNA was loaded per lane on formaldehyde-1.5% agarose gels (9). After electrophoresis, the gels were blotted onto nitrocellulose sheets and hybridized by the method of Thomas (13), except that no dextran sulfate was added to the hybridization buffer. DNA probes were labeled by nick translation (11) to a specific activity of 108 cpm/,Lg of DNA. Figure 1 depicts the structure of the mouse EP gene. Plasmid DB2-5, which has the indicated 4.5-kilobase-pair BglII fragment of the mouse EP gene inserted into the BainHI site of the plasmid vector pUC19 (12), was a gift from C. Shoemaker, Genetics Institute, Cambridge, Mass. The inserted BglII fragment contains the entire promoter and coding regions of the gene (and most of the 3' untranslated sequence). The probe used to detect EP-specific transcripts was the BamHI-EcoRI fragment or the BamHI-SmaI fragment prepared from DB2-5 by digestion and isolation from a 1% agarose gel (Fig. 1). The forme' probe is more sensitive than the latter, but in addition to EP mRNA it also hybridizes with a small nucleic acid species, present in equal amounts in all mouse cells, which migrates diffusely with the dye front in formaldehyde-agarose gels.For studies of the organ distribution of EP mRNA, female BALB/c mice aged 12 to 14 weeks and weighing 20 to 24 g were made anemic by bleeding from the retroorbital sinus. The mice were bled 0.4 ml at 36, 24, and 16 h before * Corresponding author.sacrificed by cervical dislocation. Their hematocrits just before sacrifice were 17 to 20%, whereas hematocrits of normal animals were 48 to 51%. The results...

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Hepatic Regeneration and Erythropoietin Production in the Rat

Cited by 73 publications

References 15 publications

Hif-1

Hif-1

Suppression of the Human Erythropoietin Gene Expression by the TR2 Orphan Receptor, a Member of the Steroid Receptor Superfamily

Anemia induces accumulation of erythropoietin mRNA in the kidney and liver.

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