生物
NF-κB
癌症研究
雷布
细胞生物学
转录因子
IκB激酶
作者
Hendrik Nogai,Sören-Sebastian Wenzel,Stephan Hailfinger,Michael Grau,Eva Kaergel,Volkhard Seitz,Brigitte Wollert-Wulf,Matthias Pfeifer,Annette Wolf,Mareike Frick,Kerstin Dietze,Hannelore Madle,Alexander Tzankov,Michael Hummel,Bernd Dörken,Claus Scheidereit,Martin Janz,Peter Lenz,Margot Thome,Georg Lenz
出处
期刊:Blood
[American Society of Hematology]
日期:2013-09-26
卷期号:122 (13): 2242-2250
被引量:52
标识
DOI:10.1182/blood-2013-06-508028
摘要
Constitutive activation of the nuclear factor-κ B (NF-κB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-κB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear IκB protein IκB-ζ to be upregulated in ABC compared with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IκB-ζ by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IκB-ζ knockdown demonstrated a significant downregulation of a large number of known NF-κB target genes, indicating an essential role of IκB-ζ in regulating a specific set of NF-κB target genes. To further investigate how IκB-ζ mediates NF-κB activity, we performed immunoprecipitations and detected a physical interaction of IκB-ζ with both p50 and p52 NF-κB subunits, indicating that IκB-ζ interacts with components of both the canonical and the noncanonical NF-κB pathway in ABC DLBCL. Collectively, our data demonstrate that IκB-ζ is essential for nuclear NF-κB activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies.
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