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  • Original Paper
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A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA

Oncogene volume 22, pages 3554–3561 (2003)Cite this article

Abstract

The occurrence of pathologically stable mRNAs of proto-oncogenes, growth factors and cyclins has been proposed to contribute to experimental and human oncogenesis. In normal resting cells, mRNAs containing an AU-rich element (ARE) in their 3′ untranslated region are subjected to rapid degradation. Tristetraprolin (TTP) is an RNA-binding zinc-finger protein that promotes decay of ARE-containing mRNAs. Here we report that TTP acts as a potent tumor suppressor in a v-H-ras-dependent mast cell tumor model, where tumors express abnormally stable interleukin-3 (IL-3) mRNA as part of an oncogenic autocrine loop. Premalignant v-H-ras cells were transfected with TTP and injected into syngeneic mice. TTP expression delayed tumor progression by 4 weeks, and late appearing tumors escaped suppression by loss of TTP. When transfected into a fully established tumor line, TTP reduced cloning efficiency in vitro and growth of the inoculated cells in vivo. Transgenic TTP interfered with the autocrine loop by enhancing the degradation of IL-3 mRNA with concomitant reduction of IL-3 secretion. Our data establish the ARE as an antioncogenic target in a model situation, underline the importance of mRNA stabilization in oncogenesis and show for the first time that tumor suppression can be achieved by interfering with mRNA turnover.

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Acknowledgements

We thank Renate Looser, Marco Colombi and the late Beatrice Rickenbacher for technical assistance, Asha PK Nair for help with tumor cell transfection, and Ines Raineri for critical reading of the manuscript. This work was supported by Grant # 31-57065.99 from the Swiss National Science Foundation to C.M.

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Author notes

  1. Georg Stoecklin

    Present address: Division of Rheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA

  2. Xiu-Fen Ming

    Present address: Institute of Physiology, University of Fribourg, Rue du Musée 5, CH-1700, Fribourg, Switzerland

Authors and Affiliations

  1. Institute of Medical Microbiology, University of Basel, Petersplatz 10, Basel, CH-4003, Switzerland

    Georg Stoecklin, Brigitte Gross, Xiu-Fen Ming & Christoph Moroni

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  1. Georg Stoecklin
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Correspondence to Christoph Moroni.

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Stoecklin, G., Gross, B., Ming, XF. et al. A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA. Oncogene 22, 3554–3561 (2003). https://doi.org/10.1038/sj.onc.1206418

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