Fernández-Majada V, Aguilera C, Villanueva A, Vilardell F, Robert-Moreno A, Aytés A, Real F X, Capella G, Mayo M W, Espinosa L, Bigas A
Centre Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge, Gran Via Km 2.7, Hospitalet, 08907 Barcelona, Spain.
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):276-81. doi: 10.1073/pnas.0606476104. Epub 2006 Dec 26.
Nuclear functions for IkappaB 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, IKKalpha 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 IKKalpha 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.
最近已描述了IκB激酶（IKK）的核功能，包括组蛋白H3和核共抑制因子的磷酸化。在此，我们表明IKK在结肠直肠肿瘤中被激活，同时存在异常定位于细胞质中的磷酸化SMRT（视黄酸和甲状腺激素受体沉默介质）共抑制因子。在这些肿瘤中，IKKα与特定Notch靶标的染色质结合，导致SMRT释放。用BAY11-7082或通过表达显性负性IKKα消除IKK活性可恢复SMRT与Notch靶基因的结合，导致特定基因的抑制。最后，BAY11-7082显著减小了植入裸鼠的结肠直肠癌异种移植物（CRC-Xs）的肿瘤大小。
