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

Osamu Tetsu and Frank McCormick ()
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Osamu Tetsu: University of California, San Francisco, School of Medicine, Cancer Research Institute
Frank McCormick: University of California, San Francisco, School of Medicine, Cancer Research Institute

Nature, 1999, vol. 398, issue 6726, 422-426

Abstract: 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.

Date: 1999
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DOI: 10.1038/18884

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