beta-catenin regulates expression of cyclin D1 in colon carcinoma cells

Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene oc cur in most human colon cancers(1) Loss of functional APC protein results i n the accumulation of beta-catenin(2). Mutant forms of beta-catenin have be en discovered in colon cancers that retain wild-type APC genes(3,4), and al so in melanomas(5), medulloblastomas(6), prostate cancer(7) and gastric(8) and hepatocellular(9,10) carcinomas. The accumulation of beta-catenin activ ates genes that are responsive to transcription factors of the TCF/LEF fami ly, with which beta-catenin interacts(11-15). Here we show that beta-cateni n activates transcription from the cyclin D1 promoter, and that sequences w ithin the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21(ras) further activates transc ription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-ca tenin produce high levels of cyclin D1 messenger RNA and protein constituti vely. Furthermore, expression of a dominant-negative form of TCF in colon-c ancer cells strongly inhibits expression of cyclin DI without affecting exp ression of cyclin D2, cyclinE, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cy cle; this phenotype can be rescued by expression of cyclin D1 under the cyt omegalovirus promoter. Abnormal levels of beta-catenin may therefore contri bute to neoplastic transformation by causing accumulation of cyclin D1.