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

被引：254

作者：

Morris, Erick J. ^{[1
,2
]}

Ji, Jun-Yuan ^{[1
,2
]}

Yang, Fajun ^{[1
,2
,3
]}

Di Stefano, Luisa ^{[1
,2
]}

Herr, Anabel ^{[1
,2
]}

Moon, Nam-Sung ^{[1
,2
]}

Kwon, Eun-Jeong ^{[4
,5
]}

Haigis, Kevin M. ^{[1
,2
,6
]}

Naar, Anders M. ^{[1
,2
,3
]}

Dyson, Nicholas J. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Mol Oncol Lab, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Charlestown, MA 02129 USA

[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[4] Massachusetts Gen Hosp, Boston, MA 02114 USA

[5] Vincent Ctr Reprod Biol, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Ctr Canc, Lab Mol Pathol, Charlestown, MA 02129 USA

来源：

NATURE | 2008年 / 455卷 / 7212期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature07310

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1). 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.

引用

页码：552 / U67

页数：7

共 29 条

[1] Distinctions in the specificity of E2F function revealed by gene expression signatures [J].