Defective IκBα in Hodgkin cell lines with constitutively active NF-κB

被引:112
作者
Wood, KM
Roff, M
Hay, RT
机构
[1] Univ St Andrews, Sch Biol & Med Sci, St Andrews KY16 9AL, Fife, Scotland
[2] Royal Victoria Infirm, Dept Pathol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England
基金
英国惠康基金;
关键词
Hodgkin's lymphoma; NF-kappa B; I kappa B alpha;
D O I
10.1038/sj.onc.1201735
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The molecular mechanisms underlying Hodgkin's disease remain obscure, but it has been recognized that the neoplastic cells display high levels of constitutively active nuclear NF-kappa B. Here me demonstrate that although nuclear NF-kappa B is transcriptionally active, the Hodgkin cells fail to activate NF-KB dependent transcription in response to CD40 ligand, In three Hodgkin cell lines examined each had abnormalities in expression of I kappa B alpha which could account for the deregulated NF-kappa B. Although all three cell lines had greater than normal levels of I kappa B alpha mRNA no I kappa B alpha protein could be detected in the KM-H2 cells, while the L428 cell line contains a C-terminally truncated I kappa B alpha species that fails to associate with NF-kappa B. The HDLM-2 cell line contains a more slowly migrating form of I kappa B alpha that can associate with NF-kappa B, but increasing the level of this protein within the cell fails to inhibit nuclear NF-kappa B. Addition of recombinant I kappa B alpha to nuclear extracts from all three cell lines resulted in complete inhibition of NF-kappa B DNA binding activity and introduction of a plasmid expressing I kappa B alpha into the cells inhibited the transcriptional activity of an NF-kappa B dependent reporter plasmid, Thus the constitutive expression of NF-kappa B in Hodgkin cells is a direct consequence of the abnormal expression of I kappa B alpha rather than changes in NF-kappa B that render it refractory to inhibition by I kappa B proteins. These changes could, at least in part, account for the characteristic activated phenotype of Hodgkin cells and their pattern of cytokine secretion, which determine the pathological appearance and clinical manifestations of Hodgkin's disease.
引用
收藏
页码:2131 / 2139
页数:9
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