Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b.
Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which plays a major role in tumor angiogenesis. VEGF mRNA expression is controlled by hypoxia, growth factors and hormones through both transcriptional and post-transcriptional mechanisms. VEGF mRNA has a short half-life and its abundance is regulated by the binding of stabilizing (HuR, hRNP-L) and still uncharacterised destabilizing proteins to its 3'-untranslated region. Here, we report that the ACTH-regulated zinc-finger protein TIS11b and its homologs TIS11 and TIS11d interact with the 3'-untranslated region of VEGF mRNA and decrease its stability (half-life reduced from 130 to 60 min). Within the 2201 bp 3'-untranslated region of VEGF mRNA, we identified a 75 bp domain, containing two consensus AU-rich motifs, which binds TIS11b and mediates its destabilizing activity. Ribonucleoprotein (RNP) complex immunoprecipitation experiments allowed us to demonstrate that the interaction between TIS11b and VEGF 3'-untranslated region occurs in live cells. Knocking down TIS11b expression in primary adrenocortical cells with small interfering (si)RNAs clearly indicated that TIS11b participates in the control of both basal and, to a larger extent, ACTH-induced VEGF mRNA expression levels. TIS11b is the first VEGF mRNA-destabilizing protein identified so far and therefore appears as a new potential target in antiangiogenic therapies.
INSERM EMI 01-05, Department of Cellular Responses and Dynamics, Commissariat à l'Energie Atomique, 17 Rue des Martyrs, F-38054 Grenoble Cedex 9, France.
Delphine
D
Ciais
Nadia
N
Cherradi
Sabine
S
Bailly
Emilie
E
Grenier
Edurne
E
Berra
Jacques
J
Pouyssegur
Jonathan
J
Lamarre
Jean-Jacques
JJ
Feige
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D051817:Butyrate Response Factor 1; D002417:Cattle; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051816:Tristetraprolin; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D020413:3' Untranslated Regions; D051817:Butyrate Response Factor 1; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D051816:Tristetraprolin; D042461:Vascular Endothelial Growth Factor A; C497553:Zfp36 protein, mouse; C497554:Zfp36 protein, rat; C497555:Zfp36l1 protein, rat