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

Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):9948-9953. doi: 10.1073/pnas.1705338114. Epub 2017 Aug 29.

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.

Keywords: Von Hippel Lindau; glucocorticoid signaling; hypoxia-inducible factor; liver; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

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

Substances

  • Glucocorticoids
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Trans-Activators
  • hif1aa protein, zebrafish
  • Ubiquitin-Protein Ligases
  • Ligases