1. Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA
2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Massachusetts General Hospital and The Vincent Center for Reproductive Biology, 55 Fruit Street, Their 901, Boston, Massachusetts 02114, USA
4. Laboratory of Molecular Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA
5. These authors contributed equally to this work.

Correspondence to: Nicholas J. Dyson¹ Correspondence and requests for materials should be addressed to N.J.D. (Email: dyson@helix.mgh.harvard.edu).

Abstract

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 -catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses -catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key -catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on -catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein¹. Elevated levels of CDK8 protect -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 -catenin.

1. Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA
2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Massachusetts General Hospital and The Vincent Center for Reproductive Biology, 55 Fruit Street, Their 901, Boston, Massachusetts 02114, USA
4. Laboratory of Molecular Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA
5. These authors contributed equally to this work.

Correspondence to: Nicholas J. Dyson¹ Correspondence and requests for materials should be addressed to N.J.D. (Email: dyson@helix.mgh.harvard.edu).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.