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Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression

Oncogene volume 22, pages 6395–6407 (2003)Cite this article

Abstract

The transcription factor Cdx1 regulates intestine-specific gene expression and enterocyte differentiation. It has been hypothesized to play a role in regulating intestinal cell proliferation; however, the mechanism for this effect remains elusive. In a prior study, we demonstrated that Cdx1 expression reduced the proliferation of a nontransformed intestinal cell line. This study tests the hypothesis that Cdx1 expression inhibits colon cancer cell proliferation by reducing cyclin D1 gene expression. Cdx1 expression markedly reduced cancer cell proliferation and DNA synthesis and induced an accumulation of cells in G0/G1. A transcriptionally inactive Cdx1 mutant could not elicit this effect, suggesting that it required Cdx1 transcriptional activity. Cdx1 expression increased the hypophosphorylation of the retinoblastoma (pRb) and p130 proteins. Reductions in G1 cyclin-dependant kinase (cdk) activity accompanied this effect. Cyclin D1 mRNA and protein levels were diminished by Cdx1 expression. Restoration of cyclin D1 expression reversed the G0/G1 block and induced pRb hyperphosphorylation. Lastly, Cdx1 expression did not alter cyclin D1 mRNA stability but did reduce cyclin D1 promoter activity, suggesting that Cdx1 acts to diminish cyclin D1 gene transcription. We conclude that Cdx1 reduces the proliferation of human colon cancer cells by reducing cyclin D1 gene transcription.

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Abbreviations

CDX1, CDX2:

human genes

Cdx1, Cdx2:

mouse genes or species not specified

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Acknowledgements

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants PO1-DK49210 (project to P Traber and S Silberg) and DK02695-02 (J Lynch), Pilot Project awards from the McCabe Fund (to J Lynch) and Center for Molecular Studies in Digestive and Liver Disease (to J Lynch), and the Morphology, Cell Culture, and Molecular Biology Cores of the NIH/NIDDK Center for Molecular Studies in Digestive Diseases at the University of Pennsylvania (P30-DK50306). This work was also supported in part by Grant IRG-78-002-25 from the American Cancer Society (J Lynch).

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  1. Peter Traber

    Present address: Baylor college of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

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  1. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA

    John Lynch, Matthew Keller, Rong-Jun Guo, Donald Yang & Peter Traber

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  1. John Lynch
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Correspondence to John Lynch.

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Lynch, J., Keller, M., Guo, RJ. et al. Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression. Oncogene 22, 6395–6407 (2003). https://doi.org/10.1038/sj.onc.1206770

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