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RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53

Oncogene volume 23, pages 5476–5486 (2004)Cite this article

Abstract

The mammalian Runx gene family (Runx1–3) are transcription factors that play essential, lineage-specific roles in development. A growing body of evidence implicates these genes as mutational targets in cancer where, in different contexts, individual family members have been reported to act as tumour suppressors, dominant oncogenes or mediators of metastasis. We are exploring these paradoxical observations by ectopic expression of RUNX genes in primary murine embryonic fibroblasts where, in common with a number of other dominant oncogenes, RUNX1 induces senescence-like growth arrest in the presence of an intact p19ARF-p53 pathway. We now report that, in MEFs lacking functional p53, RUNX1 has apparently prooncogenic effects on cell growth that include cytoskeletal reorganization, reduced contact inhibition at confluence and accelerated tumour expansion in vivo. On the other hand, RUNX1 conferred no obvious growth advantage at low cell density and actually delayed entry of primary MEFs into S phase. We also found that ectopic RUNX1 interferes with the morphological and growth responses of p53-null MEFs to TGFβ indicating that these effects are mediated by overlapping pathways. These observations help to elucidate the context-dependent consequences of loss and gain of Runx activity.

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Acknowledgements

We thank Dr B Linggi and Dr S Hiebert for providing pBabe-AML plasmid and helpful discussions. This work was supported by Cancer Research UK and the Leukaemia Research Fund of Great Britain. ADF is a Leukemia and Lymphoma Society Scholar.

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Authors and Affiliations

  1. Molecular Oncology Laboratory, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, UK

    Sandy F Wotton, Karen Blyth, Anna Kilbey, Alma Jenkins, Anne Terry, James C Neil & Ewan R Cameron

  2. Division of Pediatric Oncology, John Hopkins University, Cancer Research Building, Room 253, 1650 Orleans Street, Baltimore, 21231, MD, USA

    Florence Bernardin-Fried & Alan D Friedman

  3. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., Seattle, 98109, WA, USA

    Euan W Baxter

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  1. Sandy F Wotton
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Correspondence to Sandy F Wotton.

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Wotton, S., Blyth, K., Kilbey, A. et al. RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53. Oncogene 23, 5476–5486 (2004). https://doi.org/10.1038/sj.onc.1207729

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