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

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 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 oncoprotein1. 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.

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Figure 1: Functional antagonism between E2F1 and β-catenin/TCF-signalling.
Figure 2: E2F1 abrogates Wnt signalling by modulating β-catenin target gene expression and inducing the GSK3-independent degradation of β-catenin.
Figure 3: pRB inactivation abrogates β-catenin/TCF-dependent transcription.
Figure 4: CDK8 antagonizes E2F1 activity.

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Acknowledgements

We thank many investigators for their gifts of cell lines, plasmids and fly stocks, especially S. Artavanis-Tsakonas. We thank D. Rennie and the Massachusetts General Hospital Cutaneous Biology Research Center Transgenic Fly Core for embryo injections, and B. Fowle for his help with SEM imaging. We thank A. McClatchey, J. Settleman, C. Seum and T. Orr-Weaver for their gifts of antibodies. We thank our colleagues at the Massachusetts General Hospital (MGH) Cancer Center for discussions. E.J.M. and J.-Y.J. are supported in part by a Ruth L. Kirschstein Award and a Tosteson Postdoctoral Fellowship, respectively. L.D.S. is supported by the MGH ECOR Fund for Medical Discovery. N.-S.M. is a Leukemia and Lymphoma Society Special Fellow. K.M.H. was supported by a Career Development award from the Harvard Gastrointestinal Specialized Program of Research Excellence (GI-SPORE) (P50-CA127003). N.J.D. was supported by a scholarship from the Saltonstall Foundation. This study was supported by grants from the National Institutes of Health to N.J.D. (GM81607, GM053203) and A.M.N. (GM071449).

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Correspondence to Nicholas J. Dyson.

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Morris, E., Ji, JY., Yang, F. et al. E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552–556 (2008). https://doi.org/10.1038/nature07310

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