细胞核内的IKK活性导致结直肠癌中Notch依赖的基因表达失调。
Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer.
作者信息
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
机构信息
Centre Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge, Gran Via Km 2.7, Hospitalet, 08907 Barcelona, Spain.
出版信息
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):276-81. doi: 10.1073/pnas.0606476104. Epub 2006 Dec 26.
Abstract
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.
摘要
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。
相似文献
1
Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer.细胞核内的IKK活性导致结直肠癌中Notch依赖的基因表达失调。
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):276-81. doi: 10.1073/pnas.0606476104. Epub 2006 Dec 26.
2
Regulation and function of IKK and IKK-related kinases.IKK及IKK相关激酶的调控与功能
Sci STKE. 2006 Oct 17;2006(357):re13. doi: 10.1126/stke.3572006re13.
3
IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300.IκB激酶α介导的SMRT去抑制增强了p300对RelA/p65的乙酰化作用。
Mol Cell Biol. 2006 Jan;26(2):457-71. doi: 10.1128/MCB.26.2.457-471.2006.
4
A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer.IKKα 的截短形式负责结直肠癌中特定的核 IKK 活性。
Cell Rep. 2012 Oct 25;2(4):840-54. doi: 10.1016/j.celrep.2012.08.028. Epub 2012 Oct 4.
5
Role of IKK and oscillatory NFkappaB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells.IKK和振荡性NFκB动力学在RKO结肠癌细胞中MMP-9基因表达及对5-氟尿嘧啶化疗耐药中的作用
Mol Carcinog. 2007 May;46(5):402-13. doi: 10.1002/mc.20288.
6
Extending the nuclear roles of IkappaB kinase subunits.扩展IκB激酶亚基的核功能
Biochem Pharmacol. 2006 Oct 30;72(9):1081-9. doi: 10.1016/j.bcp.2006.06.017. Epub 2006 Jul 18.
7
Nuclear corepressor and silencing mediator of retinoic and thyroid hormone receptors corepressor expression is incompatible with T(3)-dependent TRH regulation.视黄酸和甲状腺激素受体共抑制因子的核共抑制因子和沉默介质共抑制因子的表达与三碘甲状腺原氨酸（T3）依赖的促甲状腺激素释放激素（TRH）调节不相容。
Endocrinology. 2001 Dec;142(12):5321-31. doi: 10.1210/endo.142.12.8531.
8
The IKK-neutralizing compound Bay11 kills supereffector CD8 T cells by altering caspase-dependent activation-induced cell death.IKK 中和化合物 Bay11 通过改变半胱天冬酶依赖性激活诱导的细胞死亡来杀死超效应 CD8 T 细胞。
J Leukoc Biol. 2009 Jan;85(1):175-85. doi: 10.1189/jlb.0408248. Epub 2008 Oct 15.
9
The silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full estrogen receptor alpha transcriptional activity.维甲酸和甲状腺激素受体沉默介质（SMRT）共抑制因子是雌激素受体α充分转录活性所必需的。
Mol Cell Biol. 2007 Sep;27(17):5933-48. doi: 10.1128/MCB.00237-07. Epub 2007 Jun 25.
10
The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus.核因子κB激活途径：从细胞膜到细胞核信息传递的范例。
Sci STKE. 1999 Oct 26;1999(5):RE1. doi: 10.1126/stke.1999.5.re1.
引用本文的文献
1
Double trouble: cytosolic and nuclear IKKα in cancer.双重麻烦：癌症中的胞质和核内IKKα
Open Biol. 2025 Aug;15(8):240375. doi: 10.1098/rsob.240375. Epub 2025 Aug 6.
2
NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage.NEMO对于将激酶IKKα和ATM引导至DNA损伤位点至关重要。
Sci Signal. 2025 Mar 11;18(877):eadr0128. doi: 10.1126/scisignal.adr0128.
3
Bioinformatic Analysis of Complex Genes Expression in Selected Gastrointestinal Cancers.生物信息学分析选定胃肠道癌中复杂基因的表达。
Int J Mol Sci. 2024 Sep 12;25(18):9868. doi: 10.3390/ijms25189868.
4
Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis.解析特定炎症信号通路与HIV相关结直肠癌发生机制之间的复杂相互联系。
Cancers (Basel). 2023 Jan 25;15(3):748. doi: 10.3390/cancers15030748.
5
The role of Hedgehog and Notch signaling pathway in cancer.刺猬信号通路和Notch信号通路在癌症中的作用。
Mol Biomed. 2022 Dec 15;3(1):44. doi: 10.1186/s43556-022-00099-8.
6
Targeting IKKα kinase to prevent tumor progression and therapy resistance.靶向IKKα激酶以预防肿瘤进展和治疗耐药性。
Cancer Drug Resist. 2020 Mar 21;3(3):482-490. doi: 10.20517/cdr.2019.104. eCollection 2020.
7
Notch signaling pathway: architecture, disease, and therapeutics.Notch 信号通路：结构、疾病与治疗。
Signal Transduct Target Ther. 2022 Mar 24;7(1):95. doi: 10.1038/s41392-022-00934-y.
8
Loss of LKB1-NUAK1 signalling enhances NF-κB activity in a spheroid model of high-grade serous ovarian cancer.LKB1-NUAK1 信号丢失增强了高级别浆液性卵巢癌球体模型中的 NF-κB 活性。
Sci Rep. 2022 Feb 22;12(1):3011. doi: 10.1038/s41598-022-06796-2.
9
Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer.IKK-α 的空间表达与原发性结直肠癌的突变特征和生存相关。
Br J Cancer. 2022 Jun;126(12):1704-1714. doi: 10.1038/s41416-022-01729-2. Epub 2022 Feb 16.
10
EPO activates PI3K-IKKα-CDK1 signaling pathway to promote the proliferation of Glial Cells under hypoxia environment.促红细胞生成素（EPO）激活磷脂酰肌醇-3激酶-核因子κB抑制蛋白激酶α-周期蛋白依赖性激酶1信号通路，以促进缺氧环境下神经胶质细胞的增殖。
Genet Mol Biol. 2022 Feb 11;45(1):e20210249. doi: 10.1590/1678-4685-GMB-2021-0249. eCollection 2022.
本文引用的文献
1
Nuclear factor-kappaB in cancer development and progression.核因子-κB在癌症发生发展中的作用
Nature. 2006 May 25;441(7092):431-6. doi: 10.1038/nature04870.
2
IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300.IκB激酶α介导的SMRT去抑制增强了p300对RelA/p65的乙酰化作用。
Mol Cell Biol. 2006 Jan;26(2):457-71. doi: 10.1128/MCB.26.2.457-471.2006.
3
Recent insights into the role of Notch signaling in tumorigenesis.近期对Notch信号通路在肿瘤发生中作用的见解。
Blood. 2006 Mar 15;107(6):2223-33. doi: 10.1182/blood-2005-08-3329. Epub 2005 Nov 15.
4
Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor.在MDCK上皮细胞系中，响应蜗牛转录因子的表达，基质金属蛋白酶-9（MMP-9）上调。
J Cell Sci. 2005 Aug 1;118(Pt 15):3371-85. doi: 10.1242/jcs.02465.
5
Notch signals control the fate of immature progenitor cells in the intestine.Notch信号控制肠道中未成熟祖细胞的命运。
Nature. 2005 Jun 16;435(7044):964-8. doi: 10.1038/nature03589.
6
Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.Notch/γ-分泌酶抑制可使肠隐窝和腺瘤中的增殖细胞转变为杯状细胞。
Nature. 2005 Jun 16;435(7044):959-63. doi: 10.1038/nature03659.
7
Meningioma transcript profiles reveal deregulated Notch signaling pathway.脑膜瘤转录谱揭示Notch信号通路失调。
Cancer Res. 2005 Jun 15;65(12):5070-5. doi: 10.1158/0008-5472.CAN-05-0240.
8
Alteration of SMRT tumor suppressor function in transformed non-Hodgkin lymphomas.转化型非霍奇金淋巴瘤中SMRT肿瘤抑制功能的改变。
Cancer Res. 2005 Jun 1;65(11):4554-61. doi: 10.1158/0008-5472.CAN-04-4108.
9
A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways.泛素缀合在IκB激酶途径激活和终止中的普遍作用。
EMBO Rep. 2005 Apr;6(4):321-6. doi: 10.1038/sj.embor.7400380.
10
Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation.雌激素受体介导的基因激活需要形成IKKα依赖性转录复合物。
Mol Cell. 2005 Apr 1;18(1):71-82. doi: 10.1016/j.molcel.2005.03.006.
Zotero 插件