Letters to Nature

Nature 398, 422-426 (1 April 1999) | doi:10.1038/18884; Received 30 December 1998; Accepted 17 February 1999

bold beta-Catenin regulates expression of cyclin D1 in colon carcinoma cells

Osamu Tetsu1 & Frank McCormick1

  1. University of California, San Francisco, School of Medicine, Cancer Research Institute, San Francisco, California 94143-0128, USA

Correspondence to: Frank McCormick1 Correspondence and requests for materials should be addressed to F.M. (e-mail: Email: mccormick@cc.ucsf.edu).

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 beta-catenin2. Mutant forms of beta-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 beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts11, 12, 13, 14, 15. Here we show that beta-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 beta-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 beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.