E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8

• Published in: Nature (London) 2008-09, Vol.455 (7212), p.552-556
• Main Authors: Morris, Erick J., Ji, Jun-Yuan, Yang, Fajun, Di Stefano, Luisa, Herr, Anabel, Moon, Nam-Sung, Kwon, Eun-Jeong, Haigis, Kevin M., Näär, Anders M., Dyson, Nicholas J.
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - metabolism; Apoptosis; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Biological and medical sciences; Causes of; Cell Line; Chemical properties; Cyclin-Dependent Kinase 8; Cyclin-Dependent Kinases - metabolism; DNA binding proteins; DNA-ligand interactions; E2F1 Transcription Factor - antagonists & inhibitors; E2F1 Transcription Factor - metabolism; Evaluation; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation; Genes, myc - genetics; Genetic transcription; Glycogen Synthase Kinase 3 - metabolism; Health aspects; Humanities and Social Sciences; Humans; letter; Medical sciences; multidisciplinary; Physiological aspects; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Science; Science (multidisciplinary); Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; TCF Transcription Factors - metabolism; Transcription, Genetic; Tumors; Wnt Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature07310

CCK8 and WNT signalling linked in colorectal cancer The WNT/ β-catenin signalling pathway, which normally plays a pivotal part in development, is deregulated in almost all colorectal cancers. Retinoblastoma tumour suppressor protein (pRB) is a cell-cycle regulator that is mutated in many different types of cancer. Two papers in this issue show that signalling through the WNT pathway and that mediated by pRB are highly interconnected, and that a common denominator of their deregulation is colorectal cancer. Firestein et al . combined RNAi screening for genes required for colon cancer cell proliferation with genomic data from human colon cancer to identifty CDK8 as a novel human oncogene. CDK8, a general transcriptional regulator, functions in part by enhancing the activity of the Wnt signalling pathway. Morris et al . report that E2F1, a transcription factor that is a target of pRB, is a potent and specific inhibitor of β-catenin, and that its activity is negatively regulated by CDK8. They point out that the interaction between E2F1 and β-catenin explains the long-standing paradox that pRB, an important tumour suppressor in most other contexts, is preserved in colorectal carcinomas. In an accompanying News & Views, René Bernards considers how the crosstalk between E2F and β-catenin signalling can lead to colorectal cancer. The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of β-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses β-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key β-catenin targets including c-MYC . This interaction explains why colorectal tumours, which depend on β-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein 1 . Elevated levels of CDK8 protect β-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8 , colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of β-catenin.