Abstract
Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestinal cell proliferation and differentiation. In addition, Cdx-2 is a colonic tumour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in human colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogene. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site. This decline results from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this effect is mediated by activation of the MEK1 pathway. These results indicate that oncogenic ras activation has opposite effects on Cdx-1 and Cdx-2 expression through distinct signalling pathways and they provide the first evidence for a functional link between ras activation and the downregulation of the Cdx-2 tumour-suppressor gene in colon cancer cells.
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Acknowledgements
OL and AC contributed equally to this work. This work was supported by INSERM, MENESRIPARC and the Comité Départmental du Haut-Rhin et des Hauts-de-Seine de la Ligue contre le Cancer. We thank Dr P Sassone-Corsi (INSERM U.184, Strasbourg, France) for providing the pSV-c-jun and pBK28-c-fos plasmids, Dr G Finkenzeller (University of Freiburg, Institute of Molecular Cell Biology, Freiburg, Germany) for pcDNA-PKCα, and Dr P Duprey (Université Paris VII, Paris, France) for pCdxl-34.
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Lorentz, O., Cadoret, A., Duluc, I. et al. Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras. Oncogene 18, 87–92 (1999). https://doi.org/10.1038/sj.onc.1202280
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DOI: https://doi.org/10.1038/sj.onc.1202280
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