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Crosstalk between the cell cycle regulator Cdk2 and the Cdx2 tumor suppressor at the proliferation–differentiation interface

Oncogene volume 24, pages 7953–7954 (2005)Cite this article

Colorectal cancer arises from complex genetic, epigenetic and molecular defects that result in the sequential and cumulative deregulation of cellular functions affecting cell proliferation and differentiation, survival, angiogenesis and metastasis. Among the oncogenes and tumor suppressor genes involved, the caudal-type homeobox transcription factor Cdx2 plays a key role in intestinal cell differentiation, proliferation and is implicated in colorectal cancer progression. Loss or depletion of Cdx2 occurs in human colon tumors and when induced in transgenic animals is associated with the emergence of preneoplastic lesions leading to the formation of proliferative adenoma at the adenocarcinoma transition. In the upper digestive tract, Cdx2 is now considered as an early differentiation marker of intestinal metaplasia in Barrett's epithelium and inflammatory esophageal mucosa. These pathological situations imply that both transcriptional and post-transcriptional mechanisms controlling Cdx2 levels are likely to play a key role in the determination of intestinal cell fate, differentiation and transformation. Hence, the first paper in this issue of Oncogene (Gross et al., 2005) reveals a novel and important mechanism of regulation for the Cdx2 transcription factor. This occurs via phosphorylation of the Cdx2 protein at serine 281 by cyclin-dependent kinase 2 (Cdk2), a checkpoint cell cycle regulator, controlled by cyclins A and E at the G1/S and S/G2 transitions. The Cdk2-mediated phosphorylation of Cdx2 coordinates its polyubiquitination and degradation by the proteasome. The serine residue identified as the essential target is part of a conserved motif of four evenly spaced serines (the 4S motif) similar to the one controlling β-catenin degradation by the proteasome pathway.

These findings confirm and extend those recently reported by Boulanger et al. (2005) who showed that Cdk2 interacts with and phosphorylates Cdx2 and that in human colorectal cancer cells, a combination of the proteasome inhibitor MG132 with the selective Cdk inhibitor Roscovitine (Meijer et al., 1997) remarkably increased nuclear Cdx2 levels. Gross et al. also explored the functional consequences of replacing the serines in the 4S motif by alanines, showing impacts at Cdx2 transcriptional activity and suppression of colony formation in a transformation assay.

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References

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  1. Head Unit INSERM U673, Molecular and Clinical Oncology of Human solid tumors, Université Pierre et Marie Curie (UPMC- Paris 6), Hôpital Saint-Antoine, Paris, 75571, Cedex 12, France

    Christian Gespach

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Gespach, C. Crosstalk between the cell cycle regulator Cdk2 and the Cdx2 tumor suppressor at the proliferation–differentiation interface. Oncogene 24, 7953–7954 (2005). https://doi.org/10.1038/sj.onc.1209084

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