Multilevel Regulation of HIF-1 Signaling by TTP

Mol Biol Cell. 2012 Oct;23(20):4129-41. doi: 10.1091/mbc.E11-11-0949. Epub 2012 Aug 23.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a well-studied transcription factor mediating cellular adaptation to hypoxia. It also plays a crucial role under normoxic conditions, such as in inflammation, where its regulation is less well understood. The 3'-untranslated region (UTR) of HIF-1α mRNA is among the most conserved UTRs in the genome, hinting toward posttranscriptional regulation. To identify potential trans factors, we analyzed a large compilation of expression data. In contrast to its known function of being a negative regulator, we found that tristetraprolin (TTP) positively correlates with HIF-1 target genes. Mathematical modeling predicts that an additional level of posttranslational regulation of TTP can explain the observed positive correlation between TTP and HIF-1 signaling. Mechanistic studies revealed that TTP indeed changes its mode of regulation from destabilizing to stabilizing HIF-1α mRNA upon phosphorylation by p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2. Using a model of monocyte-to-macrophage differentiation, we show that TTP-driven HIF-1α mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1α in normoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • AU Rich Elements / genetics
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Conserved Sequence / genetics
  • Gene Expression Regulation* / drug effects
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Models, Biological
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tristetraprolin / metabolism*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 3' Untranslated Regions
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Tristetraprolin
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate