Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability - PubMed (original) (raw)
. 2000 Aug 25;275(34):26484-91.
doi: 10.1074/jbc.M002104200.
Affiliations
- PMID: 10849421
- DOI: 10.1074/jbc.M002104200
Free article
Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability
G Pagès et al. J Biol Chem. 2000.
Free article
Abstract
Stability of the vascular endothelial growth factor (VEGF) mRNA is tightly regulated through its 3'-untranslated region (3'-UTR). Here, we demonstrate that VEGF mRNA levels are increased by anisomycin, a strong activator of stress-activated protein kinases. Hence, VEGF mRNA induction is inhibited by SB202190, an inhibitor of JNK and p38/HOG kinase. Furthermore, VEGF mRNA expression is increased in cells that overexpress JNK and p38/HOG by an increase in its stability. We show by two different approaches that anisomycin exerts its effect on the VEGF mRNA 3'-UTR. First, by using an in vitro mRNA degradation assay, the half-life of the VEGF mRNA 3'-UTR region transcript was found to be increased when incubated with extracts from anisomycin-treated cells; and second, the 3'-UTR was also sufficient to confer mRNA instability to the Nhe3 (Na(+)/H(+) exchanger 3) heterologous reporter gene, and anisomycin treatment stabilized the chimeric mRNA (Nhe3 fused to the VEGF mRNA 3'-UTR). This chimeric mRNA is also more stable in cells overexpressing p38/HOG and JNK that have been stimulated by anisomycin. We show that such regulation is mediated through an AU-rich region of the 3'-UTR contained within a stable hairpin structure. By RNA electrophoretic mobility shift assays, we show that this region binds proteins specifically induced by anisomycin treatment. These findings clearly demonstrate a major role of stress-activated protein kinases in the post-transcriptional regulation of VEGF.
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