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β-Catenin regulates expression of cyclin D1 in colon carcinoma cells

Abstract

Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers1. Loss of functional APC protein results in the accumulation of β-catenin2. Mutant forms of β-catenin have been discovered in colon cancersthat retain wild-type APC genes3,4, and also in melanomas5, medulloblastomas6, prostate cancer7 and gastric8 and hepatocellular9,10 carcinomas. The accumulation of β-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which β-catenin interacts11,12,13,14,15. Here we show that β-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant β-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of β-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.

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Figure 1: β-Catenin activates the cyclin D1 promoter.
Figure 2: β-catenin-responsive elements within the cyclin D1 promoter.
Figure 3: Expression of β-catenin, cyclin D1, cdc2 and cyclin A in HeLa cells expressing mutant β-catenin.
Figure 4: Effects of valine 12 Ras on transcription from the cyclin D1 promoter.
Figure 5: Repression of cyclin D1 expression by a dominant-negative TCF-4E.
Figure 6: G1 growth arrest in HCT116 colon cancer cells by dominant negative TCF-4E, and rescue by ectopic expression of cyclin D1.

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Acknowledgements

We thank J. Xie, G. Yount, P. Sabbatini and P. Rodriguez-Viciana for technical advice, H. Clevers for suggestions, and other members of the McCormick and Stokoe labs for useful discussions. This work was supported in part by the Daiichi Cancer Research Program.

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Correspondence to Frank McCormick.

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Tetsu, O., McCormick, F. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999). https://doi.org/10.1038/18884

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