scholarly journals Control of the Vascular Endothelial Growth Factor Internal Ribosome Entry Site (IRES) Activity and Translation Initiation by Alternatively Spliced Coding Sequences

2004 ◽  
Vol 279 (18) ◽  
pp. 18717-18726 ◽  
Author(s):  
Stéphanie Bornes ◽  
Mathieu Boulard ◽  
Corinne Hieblot ◽  
Catherine Zanibellato ◽  
Jason S. Iacovoni ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Translation Initiation ◽  
Internal Ribosome Entry Site ◽  
Vascular Endothelial ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Coding Sequences ◽  
Alternatively Spliced ◽  
Endothelial Growth Factor

scholarly journals The vascular endothelial growth factor mRNA contains an internal ribosome entry site

FEBS Letters ◽  
1998 ◽  
Vol 434 (3) ◽  
pp. 417-420 ◽  
Author(s):  
Diane L Miller ◽  
Justin A Dibbens ◽  
Annette Damert ◽  
Werner Risau ◽  
Mathew A Vadas ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Internal Ribosome Entry Site ◽  
Vascular Endothelial ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Endothelial Growth Factor

scholarly journals Two Independent Internal Ribosome Entry Sites Are Involved in Translation Initiation of Vascular Endothelial Growth Factor mRNA

1998 ◽  
Vol 18 (11) ◽  
pp. 6178-6190 ◽  
Author(s):  
Isabelle Huez ◽  
Laurent Créancier ◽  
Sylvie Audigier ◽  
Marie-Claire Gensac ◽  
Anne-Catherine Prats ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Vascular Endothelial ◽  
Internal Ribosome Entry ◽  
Internal Ribosome Entry Sites ◽  
Polypyrimidine Tract Binding Protein ◽  
Initiation Of Translation ◽  
Endothelial Growth Factor

ABSTRACT The mRNA of vascular endothelial growth factor (VEGF), the major angiogenic growth factor, contains an unusually long (1,038 nucleotides) and structured 5′ untranslated region (UTR). According to the classical translation initiation model of ribosome scanning, such a 5′ UTR is expected to be a strong translation inhibitor. In vitro and bicistronic strategies were used to show that the VEGF mRNA translation was cap independent and occurred by an internal ribosome entry process. For the first time, we demonstrate that two independent internal ribosome entry sites (IRESs) are present in this 5′ UTR. IRES A is located within the 300 nucleotides upstream from the AUG start codon. RNA secondary structure prediction and site-directed mutagenesis allowed the identification of a 49-nucleotide structural domain (D4) essential to IRES A activity. UV cross-linking experiments revealed that IRES A activity was correlated with binding of a 100-kDa protein to the D4 domain. IRES B is located in the first half of the 5′ UTR. An element between nucleotides 379 and 483 is required for its activity. Immunoprecipitation experiments demonstrated that a main IRES B-bound protein was the polypyrimidine tract binding protein (PTB), a well-known regulator of picornavirus IRESs. However, we showed that binding of the PTB on IRES B does not seem to be correlated with its activity. Evidence is provided of an original cumulative effect of two IRESs, probably controlled by different factors, to promote an efficient initiation of translation at the same AUG codon.

scholarly journals Translation of Vascular Endothelial Growth Factor mRNA by Internal Ribosome Entry: Implications for Translation under Hypoxia

1998 ◽  
Vol 18 (6) ◽  
pp. 3112-3119 ◽  
Author(s):  
Ilan Stein ◽  
Ahuva Itin ◽  
Paz Einat ◽  
Rami Skaliter ◽  
Zehava Grossman ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Translational Regulation ◽  
Start Codon ◽  
Efficient Production ◽  
Vascular Endothelial ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Translational Enhancers ◽  
Endothelial Growth Factor

ABSTRACT Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic growth factor that promotes compensatory angiogenesis in circumstances of oxygen shortage. The requirement for translational regulation of VEGF is imposed by the cumbersome structure of the 5′ untranslated region (5′UTR), which is incompatible with efficient translation by ribosomal scanning, and by the physiologic requirement for maximal VEGF production under conditions of hypoxia, where overall protein synthesis is compromised. Using bicistronic reporter gene constructs, we show that the 1,014-bp 5′UTR of VEGF contains a functional internal ribosome entry site (IRES). Efficient cap-independent translation is maintained under hypoxia, thereby securing efficient production of VEGF even under unfavorable stress conditions. To identify sequences within the 5′UTR required for maximal IRES activity, deletion mutants were analyzed. Elimination of the majority (851 nucleotides) of internal 5′UTR sequences not only maintained full IRES activity but also generated a significantly more potent IRES. Activity of the 163-bp long “improved” IRES element was abrogated, however, following substitution of a few bases near the 5′ terminus as well as substitutions close to the translation start codon. Both the full-length 5′UTR and its truncated version function as translational enhancers in the context of a monocistronic mRNA.

Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis

2001 ◽  
Vol 280 (6) ◽  
pp. C1367-C1374 ◽  
Author(s):  
Yuval Dor ◽  
Rinnat Porat ◽  
Eli Keshet
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Fine Tuning ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Entry Site ◽  
Vessel Occlusion ◽  
Oxygen Homeostasis ◽  
Vessel Regression ◽  
Endothelial Growth Factor

Development of microvascular networks is set to meet the metabolic requirements of the tissue they perfuse. Accordingly, impairment of oxygen homeostasis, either due to increased oxygen consumption or as a result of blood vessel occlusion, triggers compensatory neovascularization. This feedback reaction is mediated by a hypoxia- and hypoglycemia-induced vascular endothelial growth factor (VEGF). VEGF accumulates under stress as a result of increased hypoxia-inducible factor-1α-mediated transcription, stabilization of the mRNA, and the function of a hypoxia-refractory internal ribosome entry site within its 5′-untranslated region. Matching of vascular density to the metabolic needs of the tissue may include a process of hyperoxia-induced vessel regression. Thus newly formed vascular networks may undergo a natural process of vascular pruning that takes place whenever VEGF, acting as a vascular survival factor, is downregulated below the level required to sustain immature vessels. Immature vessels are particularly vulnerable and are selectively obliterated upon withdrawal of VEGF. The plasticity window for vessel regression is determined by a delay in the recruitment of periendothelial cells to the preformed endothelial plexus. Thus fine-tuning of microvascular density takes place mostly in the newly formed plexus, but the mature system is refractory to episodic changes in tissue oxygenation. These regulatory links may malfunction in certain pathological settings.

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