Open AccessNuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer
Author(s) -
Vanesa FernándezMajada,
Cristina Aguilera,
Alberto Villanueva,
Felip Vilardell,
Alexandre RobertMoreno,
Álvaro Aytés,
F.X. Real,
Gabriel Capellà,
Marty W. Mayo,
Lluís Espinosa,
Anna Bigas
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0606476104
Subject(s) - corepressor , cancer research , nuclear receptor , biology , iκb kinase , colorectal cancer , gene silencing , chromatin , histone , transcription factor , cancer , gene , genetics
Nuclear functions for IκB 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, IKKα 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 IKKα 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.