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In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation

Oncogene volume 27, pages 6806–6816 (2008)Cite this article

Abstract

c-Myc drives uncontrolled cell proliferation in various human cancers. However, in mouse embryo fibroblasts (MEFs), c-Myc also induces apoptosis by activating the p19Arf tumor suppressor pathway. Tbx2, a transcriptional repressor of p19Arf, can collaborate with c-Myc by suppressing apoptosis. MEFs overexpressing c-Myc and Tbx2 are immortal but not transformed. We have performed an unbiased genetic screen, which identified 12 oncogenes that collaborate with c-Myc and Tbx2 to transform MEFs in vitro. One of them encodes the LPA2 receptor for the lipid growth factor lysophosphatidic acid (LPA). We find that LPA1 and LPA4, but not LPA3, can reproduce the transforming effect of LPA2. Using pharmacological inhibitors, we show that the in vitro cell transformation induced by LPA receptors is dependent on the Gi-linked ERK and PI3K signaling pathways. The transforming ability of LPA1, LPA2 and LPA4 was confirmed by tumor formation assays in vivo and correlated with prolonged ERK1/2 activation in response to LPA. Our results reveal a direct role for LPA receptor signaling in cell transformation and tumorigenesis in conjunction with c-Myc and reduced p19Arf expression.

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Acknowledgements

We thank Laurens A van Meeteren for LPA receptor plasmids and advice, Wendy Lagcher for technical assistance and Nullin Divecha and Daniel S Peeper for helpful discussions. This study was supported by grants from the Dutch Cancer Society, NKI 2003-2935 (to MvL) and NKI 2003-2964 (to WHM).

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  1. C Stortelers

    Present address: 3Current address: Ablynx, Technologiepark 4, 9052 Ghent/Zwijnaarde, Belgium.,

Authors and Affiliations

  1. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    P Taghavi, E Verhoeven, J J L Jacobs, J P Lambooij, E Tanger & M van Lohuizen

  2. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    C Stortelers & W H Moolenaar

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  1. P Taghavi
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Correspondence to M van Lohuizen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Taghavi, P., Verhoeven, E., Jacobs, J. et al. In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation. Oncogene 27, 6806–6816 (2008). https://doi.org/10.1038/onc.2008.294

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