Publication Date:
2008-09-17
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148807/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morris, Erick J -- Ji, Jun-Yuan -- Yang, Fajun -- Di Stefano, Luisa -- Herr, Anabel -- Moon, Nam-Sung -- Kwon, Eun-Jeong -- Haigis, Kevin M -- Naar, Anders M -- Dyson, Nicholas J -- GM053203/GM/NIGMS NIH HHS/ -- GM071449/GM/NIGMS NIH HHS/ -- GM81607/GM/NIGMS NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- P50 CA127003-02/CA/NCI NIH HHS/ -- P50-CA127003/CA/NCI NIH HHS/ -- R01 GM053203/GM/NIGMS NIH HHS/ -- R01 GM053203-13/GM/NIGMS NIH HHS/ -- R01 GM053203-14/GM/NIGMS NIH HHS/ -- R01 GM071449/GM/NIGMS NIH HHS/ -- R01 GM071449-04/GM/NIGMS NIH HHS/ -- R01 GM081607/GM/NIGMS NIH HHS/ -- R01 GM081607-01A1/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):552-6. doi: 10.1038/nature07310. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794899" target="_blank"〉PubMed〈/a〉
Keywords:
Adenomatous Polyposis Coli Protein/metabolism
;
Apoptosis
;
Cell Line
;
Cyclin-Dependent Kinase 8
;
Cyclin-Dependent Kinases/*metabolism
;
E2F1 Transcription Factor/*antagonists & inhibitors/*metabolism
;
Gene Expression Regulation
;
Genes, myc/genetics
;
Glycogen Synthase Kinase 3/metabolism
;
Humans
;
Retinoblastoma Protein/genetics/*metabolism
;
Signal Transduction
;
TCF Transcription Factors/metabolism
;
*Transcription, Genetic
;
Wnt Proteins/metabolism
;
beta Catenin/*antagonists & inhibitors/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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