The polypyrimidine tract-binding protein stimulates HIF-1alpha IRES-mediated translation during hypoxia.

Abstract

When oxygen supply is restricted, protein synthesis is rapidly abrogated owing to inhibition of global translation. However, HIF-1alpha protein expression can persist during hypoxia, owing to an internal ribosome entry site (IRES) in the 5'-untranslated region of its mRNA. Here, we report on the molecular mechanism of HIF-1alpha IRES-mediated translation during oxygen deprivation. Using RNA affinity chromatography and UV-crosslinking experiments, we show that the polypyrimidine tract binding protein (PTB) can specifically interact with the HIF-1alpha IRES, and that this interaction is enhanced in hypoxic conditions. Overexpression of PTB enhanced HIF-1alpha IRES activity, whereas RNA interference-mediated downregula-tion of PTB protein expression inhibited HIF-1alpha IRES activity. Furthermore, hypoxia-induced stimulation of the HIF-1alpha IRES was reduced in cells in which PTB function was downregulated. In agreement with these results, the IRES activity of HIF-1alpha IRES deletion mutants that are deficient in PTB-binding could not be stimulated by oxygen deprivation. All together, our data suggest that PTB plays a stimulatory role in the IRES-mediated translation of HIF-1alpha when oxygen supply is limited.

• Authors: Bert Schepens, Sandrine A Tinton, Yanik Bruynooghe, Rudi Beyaert, Sigrid Cornelis
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 33 Issue 21 Pg. 6884-94 ( 2005) ISSN: 1362-4962 [Electronic] England
• PMID: 16396835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5' Untranslated Regions
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Pyrimidines
• Polypyrimidine Tract-Binding Protein

Topics

• 5' Untranslated Regions (chemistry, metabolism)
• Animals
• Binding Sites
• Cell Hypoxia
• Cell Line
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Mice
• Polypyrimidine Tract-Binding Protein (metabolism)
• Protein Biosynthesis
• Pyrimidines (metabolism)