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Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b

Oncogene volume 23, pages 8673–8680 (2004)Cite this article

Abstract

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.

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Abbreviations

VEGF:

vascular endothelial growth factor

TIS11:

TPA-induced sequence 11

TTP:

tristetraprolin

3′-UTR:

3′-untranslated region

ARE:

AU-rich element

DRB:

5,6-dichloro-1-d-D-ribofuranosyl benzimidazole

TNFα:

tumour necrosis factor α

GM-CSF:

granulocyte macrophage colony-stimulating factor

PVDF:

polyvinylidene fluoride

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Acknowledgements

We are indebted to Dr G Pages for providing us the pSp64-Sty plasmid. This work was supported by INSERM (EMI 01-05), University Joseph Fourier, CEA (DSV/DRDC/ANGIO), GEFLUC, Fondation pour la Recherche Médicale (grant to DC), and Association pour la Recherche sur le Cancer (project no 7626). We are indebted to the Ligue Nationale contre le Cancer for its financial support to DC (Doctoral grant, Comité de l'Isère) and NC (post-doctoral grant) and to INSERM for its support to JL (poste orange).

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Author notes

  1. Jonathan LaMarre

    Present address: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, N1G 2W1, Canada

  2. Delphine Ciais and Nadia Cherradi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular Responses and Dynamics, INSERM EMI 01-05, Commissariat à l'Energie Atomique, 17 Rue des Martyrs, Grenoble, Cedex 9, F-38054, France

    Delphine Ciais, Nadia Cherradi, Sabine Bailly, Emilie Grenier, Jonathan LaMarre & Jean-Jacques Feige

  2. Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, 33 Avenue Lacassagne, Nice, F-06189, France

    Edurne Berra & Jacques Pouyssegur

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  1. Delphine Ciais
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  2. Nadia Cherradi
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Correspondence to Jean-Jacques Feige.

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Ciais, D., Cherradi, N., Bailly, S. et al. Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Oncogene 23, 8673–8680 (2004). https://doi.org/10.1038/sj.onc.1207939

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