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

摘要

The E2F1 transcription factor can promote proliferation or apop-tosis 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)/gly-cogen 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 RBI intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect β-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining JIB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of β-catenin.