PUBLICATION

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Authors
Vettori, A., Greenald, D., Wilson, G.K., Peron, M., Facchinello, N., Markham, E., Sinnakaruppan, M., Matthews, L.C., McKeating, J.A., Argenton, F., van Eeden, F.J.M.
ID
ZDB-PUB-170831-6
Date
2017
Source
Proceedings of the National Academy of Sciences of the United States of America   114(37): 9948-9953 (Journal)
Registered Authors
Argenton, Francesco, Facchinello, Nicola, van Eeden, Freek, Vettori, Andrea
Keywords
Von Hippel Lindau, glucocorticoid signaling, hypoxia-inducible factor, liver, metabolism
MeSH Terms
  • Animals
  • Cell Hypoxia/physiology
  • Glucocorticoids/pharmacology*
  • Glucocorticoids/physiology*
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  • Ligases/metabolism
  • Liver/metabolism
  • Protein Binding
  • Signal Transduction/physiology
  • Trans-Activators/metabolism
  • Ubiquitin-Protein Ligases/metabolism
  • Zebrafish
  • von Hippel-Lindau Disease/metabolism
(all 15)
PubMed
28851829 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.
Genes / Markers
Marker Marker Type Name
actb2GENEactin, beta 2
arntGENEaryl hydrocarbon receptor nuclear translocator
egln3GENEegl-9 family hypoxia-inducible factor 3
epoaGENEerythropoietin a
fkbp5GENEFKBP prolyl isomerase 5
hif1aaGENEhypoxia inducible factor 1 subunit alpha a
hif1abGENEhypoxia inducible factor 1 subunit alpha b
hpxaGENEhemopexin a
ldhaGENElactate dehydrogenase A4
nr3c1GENEnuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
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Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment: betamethasoneProtruding-mouth
WTchemical treatment: dexamethasoneProtruding-mouth
WTchemical treatment: dexamethasoneProtruding-mouth
WT + MO4-nr3c1chemical treatment: dexamethasoneProtruding-mouth
ia20Tgchemical treatment: dexamethasoneProtruding-mouth
ia21Tgchemical treatment: dexamethasoneProtruding-mouth
ia21Tgchemical treatment: dexamethasoneProtruding-mouth
ia21Tgchemical treatment: dexamethasoneProtruding-mouth
ia21Tgchemical treatment: dexamethasoneProtruding-mouth
ia21Tgchemical treatment: dexamethasoneProtruding-mouth
1 - 10 of 55
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu2117
    		Point Mutation
    ia20TgTransgenic Insertion
      ia21TgTransgenic Insertion
        ia22TgTransgenic Insertion
          ia30
            		Insertion
            s357
              		Point Mutation
              sh144TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                arntMO1-arntMRPHLNO
                nr3c1MO4-nr3c1MRPHLNO
                1 - 2 of 2
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                Fish
                Fish
                ia20Tg
                ia21Tg
                ia21Tg; ia22Tg
                ia21Tg + MO1-arnt
                ia21Tg + MO4-nr3c1
                nr3c1ia30/ia30; ia21Tg
                nr3c1s357/s357
                nr3c1s357/s357
                nr3c1s357/s357; ia20Tg
                nr3c1s357/s357; ia21Tg
                1 - 10 of 15
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                Antibodies
                Orthology
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                mCherryEFGmCherry
                1 - 2 of 2
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                Mapping
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                Citation
                Vettori, A., Greenald, D., Wilson, G.K., Peron, M., Facchinello, N., Markham, E., Sinnakaruppan, M., Matthews, L.C., McKeating, J.A., Argenton, F., van Eeden, F.J.M. (2017) Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization. Proceedings of the National Academy of Sciences of the United States of America. 114(37):9948-9953.