Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells.

IF 6.3 2区 医学 Q1 ONCOLOGY
Neoplasia Pub Date : 2004-05-01 DOI:10.1593/NEO.03388
N. Hironaka, K. Mochida, N. Mori, M. Maeda, N. Yamamoto, S. Yamaoka
{"title":"Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells.","authors":"N. Hironaka, K. Mochida, N. Mori, M. Maeda, N. Yamamoto, S. Yamaoka","doi":"10.1593/NEO.03388","DOIUrl":null,"url":null,"abstract":"Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-kappaB (NF-kappaB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-kappaB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IkappaB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-kappaB essential modulator (NEMO), suppressed constitutive NF-kappaB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-kappaB activation operates in ATL cells. We finally show that specific inhibition of NF-kappaB by a super-repressor form of IkappaBalpha (SR-IkappaBalpha) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-kappaB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"35 1","pages":"266-78"},"PeriodicalIF":6.3000,"publicationDate":"2004-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"85","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neoplasia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1593/NEO.03388","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 85

Abstract

Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-kappaB (NF-kappaB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-kappaB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IkappaB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-kappaB essential modulator (NEMO), suppressed constitutive NF-kappaB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-kappaB activation operates in ATL cells. We finally show that specific inhibition of NF-kappaB by a super-repressor form of IkappaBalpha (SR-IkappaBalpha) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-kappaB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.
成人t细胞白血病细胞中不依赖税收的IkappaB激酶激活。
成人t细胞白血病(ATL)是一种致命的t细胞恶性肿瘤,在感染人类t细胞白血病病毒I型(HTLV-I)后长期发生。我们之前报道过核因子- kappab (NF-kappaB)在ATL细胞中被组成性激活,尽管几乎检测不到病毒蛋白的表达,包括已知持续激活NF-kappaB的Tax。在这里,我们证明不表达可检测的Tax蛋白的ATL细胞表现出组成IkappaB激酶(IKK)活性。转染研究显示IKK1的显性阴性形式,而不是IKK2或NF-kappaB必需调节剂(NEMO),抑制ATL细胞中的组成型NF-kappaB活性。这种IKK活性伴随着p52的表达升高,表明最近描述的NF-kappaB激活的非规范途径在ATL细胞中起作用。我们最终发现,在htlv -i感染的T细胞中,无论Tax表达如何,IkappaBalpha的超抑制形式(SR-IkappaBalpha)对NF-kappaB的特异性抑制都会导致细胞死亡,这为NF-kappaB在ATL细胞存活中发挥重要作用提供了明确的证据。总之,IKK复合物在ATL细胞中通过不同于税收介导的IKK激活的细胞机制被组成性激活。进一步阐明这种细胞机制将有助于建立治疗ATL的基本原理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Neoplasia
Neoplasia ONCOLOGY-
自引率
2.10%
发文量
82
期刊介绍: Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信