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The hypoxia-inducible factor-1 DNA recognition site is cAMP-responsive.


Kvietikova, I; Wenger, R H; Marti, H H; Gassmann, M (1997). The hypoxia-inducible factor-1 DNA recognition site is cAMP-responsive. Kidney International, 51(2):564-566.

Abstract

The hypoxia-inducible factor-1 (HIF-1) was first described as a DNA binding activity that specifically recognizes an 8 bp hypoxia response element (HRE) known to be essential for oxygen-regulated erythropoietin gene expression. In electrophoretic mobility shift assays (EMSAs) HIF-1 DNA binding activity is only detectable in nuclear extracts of cells cultivated in a low oxygen atmosphere. In addition to HIF-1, a constitutive DNA binding activity also specifically binds the HIF-1 probe. Based on EMSAs using competitor oligonucleotides, specific antibodies and recombinant proteins, we previously reported that the constitutive HRE binding factor is composed of ATF-1 and CREB-1. Here we show that this site is functionally responsive to the cAMP agonist 8Br-cAMP in a dose-dependent manner under hypoxic but not under normoxic conditions. These results were confirmed by using the protein kinase A (PKA) activator Sp-cAMPS and the PKA inhibitor Rp-cAMPS: while Sp-cAMPS was synergistic with hypoxia on the HIF-1 DNA recognition site, the Rp-cAMPS isomer showed no effect. Our findings suggest that the PKA-signaling pathway is enhancing oxygen-dependent gene expression via the HRE.

Abstract

The hypoxia-inducible factor-1 (HIF-1) was first described as a DNA binding activity that specifically recognizes an 8 bp hypoxia response element (HRE) known to be essential for oxygen-regulated erythropoietin gene expression. In electrophoretic mobility shift assays (EMSAs) HIF-1 DNA binding activity is only detectable in nuclear extracts of cells cultivated in a low oxygen atmosphere. In addition to HIF-1, a constitutive DNA binding activity also specifically binds the HIF-1 probe. Based on EMSAs using competitor oligonucleotides, specific antibodies and recombinant proteins, we previously reported that the constitutive HRE binding factor is composed of ATF-1 and CREB-1. Here we show that this site is functionally responsive to the cAMP agonist 8Br-cAMP in a dose-dependent manner under hypoxic but not under normoxic conditions. These results were confirmed by using the protein kinase A (PKA) activator Sp-cAMPS and the PKA inhibitor Rp-cAMPS: while Sp-cAMPS was synergistic with hypoxia on the HIF-1 DNA recognition site, the Rp-cAMPS isomer showed no effect. Our findings suggest that the PKA-signaling pathway is enhancing oxygen-dependent gene expression via the HRE.

Citations

45 citations in Web of Science®
46 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1997
Deposited On:11 Feb 2008 12:23
Last Modified:05 Apr 2016 12:18
Publisher:Nature Publishing Group
ISSN:0085-2538
Publisher DOI:https://doi.org/10.1038/ki.1997.80
PubMed ID:9027740

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