Home LiteratureArticle Details
PMID: 1924331 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 88 ·No. 19 ·1991-10-01 ·Pages 8725-9

Semenza GL, Koury ST, Nejfelt MK, Gearhart JD, Antonarakis SE

Abstract

Synthesis of erythropoietin, the primary humoral regulator of erythropoiesis, in liver and kidney is inducible by anemia or hypoxia. Analysis of human erythropoietin gene expression in transgenic mice revealed that sequences located 6-14 kilobases 5' to the gene direct expression to the kidney, whereas sequences within the immediate 3'-flanking region control hepatocyte-specific expression. Human erythropoietin transcription initiation sites were differentially utilized in liver and kidney. Inducible transgene expression was precisely targeted to peritubular interstitial cells in the renal cortex that synthesize endogenous mouse erythropoietin. These studies demonstrate that multiple erythropoietin gene regulatory elements control cell-type-specific expression and inducibility by a fundamental physiologic stimulus, hypoxia.

Related Genes
EPO
MeSH Terms
Anemia/genetics Animals Base Sequence Blotting, Northern Erythropoietin/genetics Gene Expression Regulation Genes Humans Hypoxia/genetics Kidney/physiology Liver/physiology Mice Mice, Transgenic Molecular Sequence Data Nucleic Acid Hybridization RNA, Messenger/genetics Regulatory Sequences, Nucleic Acid Restriction Mapping Transcription, Genetic
Chemicals
RNA, Messenger Erythropoietin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Semenza G L
Department of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Koury S T
Nejfelt M K
Gearhart J D
Antonarakis S E
References (25)
25 references, click to expand
  1. Diversity of alpha-fetoprotein gene expression in mice is generated by a combination of separate enhancer elements.
    Science. 1987 Jan 2;235(4784):53-8 PMID: 2432657
  2. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial.
    N Engl J Med. 1987 Jan 8;316(2):73-8 PMID: 3537801
  3. Two 3' sequences direct adult erythroid-specific expression of human beta-globin genes in transgenic mice.
    Proc Natl Acad Sci U S A. 1987 Oct;84(20):7056-60 PMID: 3478680
  4. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice.
    Genes Dev. 1987 May;1(3):268-76 PMID: 3678824
  5. The regulated expression of erythropoietin by two human hepatoma cell lines.
    Proc Natl Acad Sci U S A. 1987 Nov;84(22):7972-6 PMID: 2825172
  6. A 3' enhancer contributes to the stage-specific expression of the human beta-globin gene.
    Genes Dev. 1987 Nov;1(9):954-61 PMID: 2828176
  7. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney.
    J Clin Invest. 1988 Feb;81(2):620-3 PMID: 3339134
  8. Erythropoietin messenger RNA levels in developing mice and transfer of 125I-erythropoietin by the placenta.
    J Clin Invest. 1988 Jul;82(1):154-9 PMID: 3392205
  9. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein.
    Science. 1988 Dec 9;242(4884):1412-5 PMID: 2849206
  10. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure.
    Blood. 1989 Jan;73(1):13-6 PMID: 2910354
  11. Polycythemia in transgenic mice expressing the human erythropoietin gene.
    Proc Natl Acad Sci U S A. 1989 Apr;86(7):2301-5 PMID: 2928334
  12. Dissecting multistep tumorigenesis in transgenic mice.
    Annu Rev Genet. 1988;22:479-519 PMID: 3071256
  13. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration.
    Blood. 1989 Aug 1;74(2):645-51 PMID: 2752138
  14. Identification of the cystic fibrosis gene: chromosome walking and jumping.
    Science. 1989 Sep 8;245(4922):1059-65 PMID: 2772657
  15. Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements.
    Mol Cell Biol. 1990 Mar;10(3):930-8 PMID: 2304468
  16. Enhancement by hypoxia of human erythropoietin gene transcription in vitro.
    J Biol Chem. 1990 Jun 25;265(18):10185-8 PMID: 2162339
  17. Dominant negative regulation of the mouse alpha-fetoprotein gene in adult liver.
    Science. 1990 Dec 21;250(4988):1732-5 PMID: 1702902
  18. Localization of cells producing erythropoietin in murine liver by in situ hybridization.
    Blood. 1991 Jun 1;77(11):2497-503 PMID: 2039831
  19. Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene.
    Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5680-4 PMID: 2062846
  20. Isolation and characterization of genomic and cDNA clones of human erythropoietin.
    Nature. 1985 Feb 28-Mar 6;313(6005):806-10 PMID: 3838366
  21. Cloning and expression of the human erythropoietin gene.
    Proc Natl Acad Sci U S A. 1985 Nov;82(22):7580-4 PMID: 3865178
  22. Purification and biochemical characterization of the promoter-specific transcription factor, Sp1.
    Science. 1986 Oct 3;234(4772):47-52 PMID: 3529394
  23. Murine erythropoietin gene: cloning, expression, and human gene homology.
    Mol Cell Biol. 1986 Mar;6(3):849-58 PMID: 3773894
  24. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver.
    Mol Cell Biol. 1986 Jul;6(7):2731-3 PMID: 3785209
  25. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.88.19.8725
Published
1991-10-01
Pages
8725-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC52582
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.88.19.8725 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2