E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.
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 beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-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 beta-catenin.
Morris
Erick J
EJ
Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA.
Ji
Jun-Yuan
JY
Yang
Fajun
F
Di Stefano
Luisa
L
Herr
Anabel
A
Moon
Nam-Sung
NS
Kwon
Eun-Jeong
EJ
Haigis
Kevin M
KM
Näär
Anders M
AM
Dyson
Nicholas J
NJ
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3
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