Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 37, Pages 9948-9953Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705338114
Keywords
hypoxia-inducible factor; glucocorticoid signaling; Von Hippel Lindau; metabolism; liver
Categories
Funding
- National Institute for Health Research Birmingham Liver Biomedical Research Unit
- Medical Research Council [G1100247]
- European Union (EU) [597F3-2012-305578]
- EU [667273, ZF-HEALTH CT-2010-242048]
- European Commission [HEALTH-F4-2010-242048]
- Biology and Biotechnology Research Council [BB/M02332X/1]
- A*Star
- Associazione Italiana per la Ricerca sul Cancro [IG 10274]
- University of Leeds
- Italian National Institute of Health [GR-2011-02346749]
- BBSRC [BB/N008553/2, BB/M02332X/1, BB/N008553/1] Funding Source: UKRI
- MRC [MR/K01532X/1, G0801976, G0400802, G1100247, MC_PC_16056] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N008553/1, BB/M02332X/1, BB/N008553/2] Funding Source: researchfish
- Medical Research Council [MR/K01532X/1, 1149759, MC_PC_16056, 996678, 1483610, G1100247, G0801976, 1483629, G0400802] Funding Source: researchfish
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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.
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