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Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

被引：113
作者：
Fernandez-Majada, V.
Aguilera, C.
Villanueva, A.
Vilardell, F.
Robert-Moreno, A.
Aytes, A.
Real, F. X.
Capella, G.
Mayo, M. W.
Espinosa, L.
Bigas, A.
机构：
[1] Inst Invest Biomed Bellvitge, Ctr Mol Oncol, Barcelona 08907, Spain
[2] Inst Invest Biomed Bellvitge, Inst Catala Oncol, Lab Recerca Translac, Barcelona 08907, Spain
[3] Univ Pompeu Fabra, Inst Municipal Invest Med, Unitat Biol Celular & Mol, Barcelona 08003, Spain
[4] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 01期
关键词：
best; SMRT; corepressor;
D O I：
10.1073/pnas.0606476104
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：
Nuclear functions for I kappa B kinase (IKK), including phosphorylation of histone H3 and nuclear corepressors, have been recently described. Here, we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor that is aberrantly localized in the cytoplasm. In these tumors, IKK alpha associates to the chromatin of specific Notch targets, leading to the release of SMRT. Abrogation of IKK activity by BAY11-7082 or by expressing dominant negative IKK alpha restores the association of SMRT with Notch target genes, resulting in specific gene repression. Finally, BAY11-7082 significantly reduces tumor size in colorectal cancer xenografts (CRC-Xs) implanted in nude mice.
引用
收藏
页码：276 / 281
页数：6
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