A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation
Open accessAbstract
We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HIF-2α, HIF-3α, ARNT2, and ARNTL exhibit pronounced cell type- and tissue-specific expression patterns.
“In contrast, HIF-2α, HIF-3α, ARNT2, and ARNTL exhibit pronounced cell type– and tissue-specific expression patterns [29,63,64]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [63]
The indexed copy does not provide a passage about expression of HIF-2α, HIF-3α, ARNT2, or ARNTL. Searches for those names and for tissue-specific expression returned material about the erythropoietin enhancer and references, but no discussion of the claimed expression patterns. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Semenza, G. L., Nejfelt, M. K., Chi, S. M., & Antonarakis, S. E. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.13.5680 · Cited by 990 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 26
- Beck I., Ramirez S., Weinmann R., Caro J. Enhancer element at the 3'-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J Biol Chem. 1991 Aug 25;266(24):15563–15566. [PubMed] [Google Scholar]
- Benjamin I. J., Horie S., Greenberg M. L., Alpern R. J., Williams R. S. Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia. J Clin Invest. 1992 May;89(5):1685–1689. doi: 10.1172/JCI115768. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Beru N., McDonald J., Lacombe C., Goldwasser E. Expression of the erythropoietin gene. Mol Cell Biol. 1986 Jul;6(7):2571–2575. doi: 10.1128/mcb.6.7.2571-2575.1986. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Costa-Giomi P., Caro J., Weinmann R. Enhancement by hypoxia of human erythropoietin gene transcription in vitro. J Biol Chem. 1990 Jun 25;265(18):10185–10188. [PubMed] [Google Scholar]
- David M., Daveran M. L., Batut J., Dedieu A., Domergue O., Ghai J., Hertig C., Boistard P., Kahn D. Cascade regulation of nif gene expression in Rhizobium meliloti. Cell. 1988 Aug 26;54(5):671–683. doi: 10.1016/s0092-8674(88)80012-6. [DOI] [PubMed] [Google Scholar] · DOI
- Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Eckardt K. U., Ratcliffe P. J., Tan C. C., Bauer C., Kurtz A. Age-dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest. 1992 Mar;89(3):753–760. doi: 10.1172/JCI115652. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Gilles-Gonzalez M. A., Ditta G. S., Helinski D. R. A haemoprotein with kinase activity encoded by the oxygen sensor of Rhizobium meliloti. Nature. 1991 Mar 14;350(6314):170–172. doi: 10.1038/350170a0. [DOI] [PubMed] [Google Scholar] · DOI
- Goldberg M. A., Dunning S. P., Bunn H. F. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science. 1988 Dec 9;242(4884):1412–1415. doi: 10.1126/science.2849206. [DOI] [PubMed] [Google Scholar] · DOI
- Goldberg M. A., Gaut C. C., Bunn H. F. Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. Blood. 1991 Jan 15;77(2):271–277. [PubMed] [Google Scholar]
- Goldberg M. A., Glass G. A., Cunningham J. M., Bunn H. F. The regulated expression of erythropoietin by two human hepatoma cell lines. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7972–7976. doi: 10.1073/pnas.84.22.7972. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Gregor P. D., Sawadogo M., Roeder R. G. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 1990 Oct;4(10):1730–1740. doi: 10.1101/gad.4.10.1730. [DOI] [PubMed] [Google Scholar] · DOI
- Jacobs K., Shoemaker C., Rudersdorf R., Neill S. D., Kaufman R. J., Mufson A., Seehra J., Jones S. S., Hewick R., Fritsch E. F. Isolation and characterization of genomic and cDNA clones of human erythropoietin. 1985 Feb 28-Mar 6Nature. 313(6005):806–810. doi: 10.1038/313806a0. [DOI] [PubMed] [Google Scholar] · DOI
- Kourembanas S., Hannan R. L., Faller D. V. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest. 1990 Aug;86(2):670–674. doi: 10.1172/JCI114759. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Kourembanas S., Marsden P. A., McQuillan L. P., Faller D. V. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest. 1991 Sep;88(3):1054–1057. doi: 10.1172/JCI115367. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Koury S. T., Bondurant M. C., Koury M. J., Semenza G. L. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991 Jun 1;77(11):2497–2503. [PubMed] [Google Scholar]
- Koury S. T., Koury M. J., Bondurant M. C., Caro J., Graber S. E. 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):645–651. [PubMed] [Google Scholar]
- Monson E. K., Weinstein M., Ditta G. S., Helinski D. R. The FixL protein of Rhizobium meliloti can be separated into a heme-binding oxygen-sensing domain and a functional C-terminal kinase domain. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4280–4284. doi: 10.1073/pnas.89.10.4280. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- När A. M., Boutin J. M., Lipkin S. M., Yu V. C., Holloway J. M., Glass C. K., Rosenfeld M. G. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell. 1991 Jun 28;65(7):1267–1279. doi: 10.1016/0092-8674(91)90021-p. [DOI] [PubMed] [Google Scholar] · DOI
- Pugh C. W., Tan C. C., Jones R. W., Ratcliffe P. J. Functional analysis of an oxygen-regulated transcriptional enhancer lying 3' to the mouse erythropoietin gene. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10553–10557. doi: 10.1073/pnas.88.23.10553. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Schuster S. J., Badiavas E. V., Costa-Giomi P., Weinmann R., Erslev A. J., Caro J. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood. 1989 Jan;73(1):13–16. [PubMed] [Google Scholar]
- Schuster S. J., Wilson J. H., Erslev A. J., Caro J. Physiologic regulation and tissue localization of renal erythropoietin messenger RNA. Blood. 1987 Jul;70(1):316–318. [PubMed] [Google Scholar]
- Semenza G. L., Dureza R. C., Traystman M. D., Gearhart J. D., Antonarakis S. E. Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements. Mol Cell Biol. 1990 Mar;10(3):930–938. doi: 10.1128/mcb.10.3.930-938.1990. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Semenza G. L., Koury S. T., Nejfelt M. K., Gearhart J. D., Antonarakis S. E. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8725–8729. doi: 10.1073/pnas.88.19.8725. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Semenza G. L., Traystman M. D., Gearhart J. D., Antonarakis S. E. Polycythemia in transgenic mice expressing the human erythropoietin gene. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2301–2305. doi: 10.1073/pnas.86.7.2301. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Umesono K., Murakami K. K., Thompson C. C., Evans R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. doi: 10.1016/0092-8674(91)90020-y. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
Cited by
Sorted by citations
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Self-citationActivation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981 · see citing works
Self-citationSies, H., Berndt, C., & Jones, D. P. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045037 · Cited by 3,520 · see citing works
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
Self-citationThe role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy
Muz, B., de la Puente, P., Azab, F., & Azab, A. K. (2015) · Hypoxia · doi:10.2147/hp.s93413 · Cited by 2,066 · see citing works
Huang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7987 · Cited by 2,113 · see citing works
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · see citing works
Regulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
Self-citationMitochondrial reactive oxygen species trigger hypoxia-induced transcription
Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., & Schumacker, P. T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11715 · Cited by 1,926 · see citing works
HIF-1: mediator of physiological and pathophysiological responses to hypoxia
Semenza, G. L. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.4.1474 · Cited by 1,822 · see citing works
Self-citationSemenza, G. L., Jiang, B.-H., Leung, S. W., Passantino, R., Concordet, J.-P., Maire, P., & Giallongo, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32529 · Cited by 1,752 · see citing works
Self-citationSalceda, S., & Caro, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.36.22642 · Cited by 1,674 · see citing works
Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia
Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., & Semenza, G. L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800102200 · Cited by 1,601 · see citing works
Self-citationRetractedNormalization of the Vasculature for Treatment of Cancer and Other Diseases
Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011) · Physiological Reviews · doi:10.1152/physrev.00038.2010 · Cited by 1,605 · see citing works
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612 · see citing works
General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.
Wang, G. L., & Semenza, G. L. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4304 · Cited by 1,468 · see citing works
Self-citationWenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135 · see citing works
Dimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1
Jiang, B.-H., Rue, E., Wang, G. L., Roe, R., & Semenza, G. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.17771 · Cited by 1,106 · see citing works
Self-citationHypoxia-inducible factor 1: master regulator of O2 homeostasis
Semenza, G. L. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80016-6 · Cited by 1,092 · see citing works
Self-citationMaxwell, P. H., Dachs, G. U., Gleadle, J. M., Nicholls, L. G., Harris, A. L., Stratford, I. J., Hankinson, O., Pugh, C. W., & Ratcliffe, P. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.15.8104 · Cited by 1,084 · see citing works
Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response
Dewhirst, M. W., Cao, Y., & Moeller, B. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2397 · Cited by 1,022 · see citing works
Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., & Fujii-Kuriyama, Y. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4273 · Cited by 1,016 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · Genes & Development · doi:10.1101/gad.14.1.34 · Cited by 967 · see citing works
Self-citationWeidemann, A., & Johnson, R. S. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.12 · Cited by 941 · see citing works
Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (2009) · Physiology · doi:10.1152/physiol.00045.2008 · Cited by 926 · see citing works
Self-citationAH RECEPTOR SIGNALING PATHWAYS
Schmidt, J. V., & Bradfield, C. A. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.55 · Cited by 899 · see citing works
Guzy, R. D., & Schumacker, P. T. (2006) · Experimental Physiology · doi:10.1113/expphysiol.2006.033506 · Cited by 881 · see citing works
An essential role for p300/CBP in the cellular response to hypoxia
Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., & Livingston, D. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.12969 · Cited by 790 · see citing works
The role of HIF in immunity and inflammation
McGettrick, A. F., & O’Neill, L. A. J. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.002 · Cited by 768 · see citing works
Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes
Gerber, H.-P., Condorelli, F., Park, J., & Ferrara, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.38.23659 · Cited by 794 · see citing works
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Lee, P. J., Jiang, B.-H., Chin, B. Y., Iyer, N. V., Alam, J., Semenza, G. L., & Choi, A. K. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.9.5375 · Cited by 782 · see citing works
Self-citationWang, G., & Semenza, G. (1993) · Blood · doi:10.1182/blood.v82.12.3610.3610 · Cited by 766 · see citing works
Self-citationHigh-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2011) · Blood · doi:10.1182/blood-2010-10-314427 · Cited by 724 · see citing works
Lactate as a fulcrum of metabolism
Brooks, G. A. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101454 · Cited by 724 · see citing works
Interdependence of hypoxic and innate immune responses
Nizet, V., & Johnson, R. S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2607 · Cited by 708 · see citing works
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663 · see citing works
Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α
Soeda, A., Park, M., Lee, D., Mintz, A., Androutsellis-Theotokis, A., McKay, R. D., Engh, J., Iwama, T., Kunisada, T., Kassam, A. B., et al. (2009) · Oncogene · doi:10.1038/onc.2009.252 · Cited by 656 · see citing works
Caniggia, I., Mostachfi, H., Winter, J., Gassmann, M., Lye, S. J., Kuliszewski, M., & Post, M. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8316 · Cited by 644 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α
Jiang, B.-H., Zheng, J. Z., Leung, S. W., Roe, R., & Semenza, G. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19253 · Cited by 629 · see citing works
Self-citationZimna, A., & Kurpisz, M. (2015) · BioMed Research International · doi:10.1155/2015/549412 · Cited by 604 · see citing works
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30117 · Cited by 596 · see citing works
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1
Semenza, G. L. (2007) · Biochemical Journal · doi:10.1042/bj20070389 · Cited by 541 · see citing works
Self-citationRegulation of tumor pH and the role of carbonic anhydrase 9
Swietach, P., Vaughan-Jones, R. D., & Harris, A. L. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9064-0 · Cited by 539 · see citing works
Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors
Sitkovsky, M., & Lukashev, D. (2005) · Nature Reviews Immunology · doi:10.1038/nri1685 · Cited by 518 · see citing works
The effect of HIF on metabolism and immunity
Taylor, C. T., & Scholz, C. C. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00587-8 · Cited by 517 · see citing works
2-Oxoglutarate-Dependent Oxygenases
Islam, M. S., Leissing, T. M., Chowdhury, R., Hopkinson, R. J., & Schofield, C. J. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044724 · Cited by 472 · see citing works
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468 · see citing works
Giatromanolaki, A., Koukourakis, M. I., Sivridis, E., Turley, H., Talks, K., Pezzella, F., Gatter, K. C., & Harris, A. L. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.2018 · Cited by 478 · see citing works
Krebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444 · see citing works
Shah, Y. M., Matsubara, T., Ito, S., Yim, S.-H., & Gonzalez, F. J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.012 · Cited by 431 · see citing works
Kallio, P. J., Pongratz, I., Gradin, K., McGuire, J., & Poellinger, L. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.11.5667 · Cited by 415 · see citing works
Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1
Rolfs, A., Kvietikova, I., Gassmann, M., & Wenger, R. H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.32.20055 · Cited by 401 · see citing works
Angiogenesis in the atherosclerotic plaque
Camaré, C., Pucelle, M., Nègre-Salvayre, A., & Salvayre, R. (2017) · Redox Biology · doi:10.1016/j.redox.2017.01.007 · Cited by 401 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Identification of a hypoxia response element in the transferrin receptor gene
Lok, C. N., & Ponka, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24147 · Cited by 380 · see citing works
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation
McIntosh, B. E., Hogenesch, J. B., & Bradfield, C. A. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135922 · Cited by 352 · see citing works
Hypoxic regulation of erythropoiesis and iron metabolism
Haase, V. H. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00174.2010 · Cited by 347 · see citing works
Regulation of Metabolism by Hypoxia-Inducible Factor 1
Semenza, G. L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010678 · Cited by 342 · see citing works
Self-citationHIF-1 regulation: not so easy come, easy go
Koh, M. Y., Spivak-Kroizman, T. R., & Powis, G. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.08.002 · Cited by 339 · see citing works
Mitochondrial reactive oxygen species regulate hypoxic signaling
Hamanaka, R. B., & Chandel, N. S. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.08.005 · Cited by 332 · see citing works
The hypoxic tumour microenvironment and metastatic progression
Subarsky, P., & Hill, R. P. (2003) · Clinical & Experimental Metastasis · doi:10.1023/a:1022939318102 · Cited by 327 · see citing works
Mechanisms of hypoxia signalling: new implications for nephrology
Schödel, J., & Ratcliffe, P. J. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0182-z · Cited by 309 · see citing works
Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia
Kapitsinou, P. P., Liu, Q., Unger, T. L., Rha, J., Davidoff, O., Keith, B., Epstein, J. A., Moores, S. L., Erickson-Miller, C. L., & Haase, V. H. (2010) · Blood · doi:10.1182/blood-2010-02-270322 · Cited by 307 · see citing works
Oxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
Ratcliffe, P. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251470 · Cited by 294 · see citing works
Mitochondria and cellular oxygen sensing in the HIF pathway
Taylor, C. T. (2008) · Biochemical Journal · doi:10.1042/bj20071249 · Cited by 298 · see citing works
Pharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288 · see citing works
Self-citationRole of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency
Mukhopadhyay, C. K., Mazumder, B., & Fox, P. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000636200 · Cited by 274 · see citing works
Role of Prolyl Hydroxylation in Oncogenically Stabilized Hypoxia-inducible Factor-1α
Chan, D. A., Sutphin, P. D., Denko, N. C., & Giaccia, A. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206922200 · Cited by 264 · see citing works
Erythropoietin regulates tumour growth of human malignancies
Yasuda, Y. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg060 · Cited by 257 · see citing works
HIF-1 in cancer therapy: two decade long story of a transcription factor
Soni, S., & Padwad, Y. S. (2017) · Acta Oncologica · doi:10.1080/0284186x.2017.1301680 · Cited by 251 · see citing works
Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors
Robey, I. F., Lien, A. D., Welsh, S. J., Baggett, B. K., & Gillies, R. J. (2005) · Neoplasia · doi:10.1593/neo.04430 · Cited by 251 · see citing works
Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00848-6 · Cited by 245 · see citing works
Hypoxia, HIF-1, and the Pathophysiologi of Common Human Diseases
Semenza, G. L., Agani, F., Feldser, D., Lyer, N., Kotch, L., Laughner, E., & Yu, 1. (2006) · Advances in Experimental Medicine and Biology · doi:10.1007/0-306-46825-5_12 · Cited by 241 · see citing works
Self-citationHayashi, M., Sakata, M., Takeda, T., Yamamoto, T., Okamoto, Y., Sawada, K., Kimura, A., Minekawa, R., Tahara, M., Tasaka, K., et al. (2004) · Journal of Endocrinology · doi:10.1677/joe.1.05599 · Cited by 234 · see citing works
Luo, W., Zhong, J., Chang, R., Hu, H., Pandey, A., & Semenza, G. L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.068577 · Cited by 232 · see citing works
Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia
Sogawa, K., Numayama-Tsuruta, K., Ema, M., Abe, M., Abe, H., & Fujii-Kuriyama, Y. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7368 · Cited by 224 · see citing works
Luo, W., Chang, R., Zhong, J., Pandey, A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217394109 · Cited by 228 · see citing works
Self-citationEhrismann, D., Flashman, E., Genn, D. N., Mathioudakis, N., Hewitson, K. S., Ratcliffe, P. J., & Schofield, C. J. (2007) · Biochemical Journal · doi:10.1042/bj20061151 · Cited by 225 · see citing works
Molecular pathways: hypoxia response in immune cells fighting or promoting cancer
Palazón, A., Aragonés, J., Morales-Kastresana, A., de Landázuri, M. O., & Melero, I. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1591 · Cited by 214 · see citing works
Melillo, G., Taylor, L. S., Brooks, A., Musso, T., Cox, G. W., & Varesio, L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.18.12236 · Cited by 201 · see citing works
Regulation of Vascular Endothelial Growth Factor Expression by Advanced Glycation End Products
Treins, C., Giorgetti-Peraldi, S., Murdaca, J., & Van Obberghen, E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106534200 · Cited by 191 · see citing works
From oxygen to erythropoietin: Relevance of hypoxia for retinal development, health and disease
Caprara, C., & Grimm, C. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.11.003 · Cited by 176 · see citing works
Hypoxia-inducible factors link iron homeostasis and erythropoiesis
Shah, Y. M., & Xie, L. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.12.031 · Cited by 187 · see citing works
Pagé, E. L., Chan, D. A., Giaccia, A. J., Levine, M., & Richard, D. E. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-06-0612 · Cited by 181 · see citing works
Li, X., & Fan, Z. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0157 · Cited by 179 · see citing works
EPAS1 trans-activation during hypoxia requires p42/p44 MAPK
Conrad, P. W., Freeman, T. L., Beitner-Johnson, D., & Millhorn, D. E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.47.33709 · Cited by 178 · see citing works
Rajakumar, A., & Conrad, K. P. (2000) · Biology of Reproduction · doi:10.1095/biolreprod63.2.559 · Cited by 177 · see citing works
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177 · see citing works
Shah, Y. M., Ito, S., Morimura, K., Chen, C., Yim, S., Haase, V. H., & Gonzalez, F. J. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.009 · Cited by 168 · see citing works
Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism
Brooks, G. A., Osmond, A. D., Arevalo, J. A., Duong, J. J., Curl, C. C., Moreno-Santillan, D. D., & Leija, R. G. (2023) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00497.2022 · Cited by 171 · see citing works
Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer
Yamamoto, Y., Ibusuki, M., Okumura, Y., Kawasoe, T., Kai, K., Iyama, K., & Iwase, H. (2008) · Breast Cancer Research and Treatment · doi:10.1007/s10549-007-9742-1 · Cited by 151 · see citing works
Albanese, A., Daly, L. A., Mennerich, D., Kietzmann, T., & Sée, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010268 · Cited by 136 · see citing works
Taylor, C. T., & McElwain, J. C. (2010) · Physiology · doi:10.1152/physiol.00029.2010 · Cited by 135 · see citing works
Maintenance of redox homeostasis by hypoxia-inducible factors
Samanta, D., & Semenza, G. L. (2017) · Redox Biology · doi:10.1016/j.redox.2017.05.022 · Cited by 127 · see citing works
Self-citationDecreased Adipose Tissue Oxygenation Associates with Insulin Resistance in Individuals with Obesity
Cifarelli, V., Beeman, S. C., Smith, G. I., Yoshino, J., Morozov, D., Beals, J. W., Kayser, B. D., Watrous, J. D., Jain, M., Patterson, B. W., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci141828 · Cited by 132 · see citing works
Hypoxia and the phenomenon of immune exclusion
Pietrobon, V., & Marincola, F. M. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02667-4 · Cited by 119 · see citing works
- Authors
- Semenza, G. L., & Wang, G. L.
- Affiliations
- Johns Hopkins University (US)
- ORCID
- Semenza, G L
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1992-12
- Volume
- 12
- Issue
- 12
- Pages
- 5447-5454
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC360482
- OpenAlex
- W2135836641
- Cited by
- 2,617
- References
- 1
- Citations by year
- 2026: 15 · 2025: 49 · 2024: 72 · 2023: 97 · 2022: 119 · 2021: 129 · 2020: 120 · 2019: 96 · 2018: 91 · 2017: 99 · 2016: 97 · 2015: 111 · 2014: 107 · 2013: 112 · 2012: 104
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk039869-16)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 39869)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- erythropoietin gene, transcriptional activation, hypoxia response, de novo protein synthesis, nuclear factor binding, 3' flanking region, enhancer function, cycloheximide sensitivity, DNase I footprinting, mutagenesis
- MeSH terms
- Base Sequence, Binding Sites, Cell Line, Deoxyribonuclease I, DNA, Enhancer Elements, Genetic, Erythropoietin, Gene Expression Regulation, Humans, Molecular Sequence Data, Oxygen, Transcription Factors, Transcription, Genetic, Cell Hypoxia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
