Published online 7 December 2005
Article |
The polypyrimidine tract-binding protein stimulates HIF-1
IRES-mediated translation during hypoxia
Department for Molecular Biomedical Research, VIB—Ghent University, Unit of Molecular Signal Transduction in Inflammation B-9052 Gent-Zwijnaarde, Belgium
*To whom correspondence should be addressed at Department for Molecular Biomedical Research, VIB—Ghent University, Unit of Molecular Signal Transduction in Inflammation, Technologiepark 927, B-9052 Gent-Zwijnaarde, Belgium. Tel: +32 9 33 13 600; Fax: +32 9 33 13 609; Email: Sigrid.Cornelis{at}dmbr.ugent.be. The authors wish it to be known that Dr R. Beyaert is considered as joint senior (last) author. (contact details: Tel: +32 9 33 13 770; Fax: +32 9 33 13 609; Email: Rudi.Beyaert{at}dmbr.ugent.be)
Received November 14, 2005. Accepted November 16, 2005.
When oxygen supply is restricted, protein synthesis is rapidly abrogated owing to inhibition of global translation. However, HIF-1
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-1 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-1 IRES, and that this interaction is enhanced in hypoxic conditions. Overexpression of PTB enhanced HIF-1 IRES activity, whereas RNA interference-mediated downregula-tion of PTB protein expression inhibited HIF-1 IRES activity. Furthermore, hypoxia-induced stimulation of the HIF-1 IRES was reduced in cells in which PTB function was downregulated. In agreement with these results, the IRES activity of HIF-1 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-1 when oxygen supply is limited.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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