JCB：生科院王琛小组揭示重要转录因子NF-κB细胞核内调控新机制

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JCB：生科院王琛小组揭示重要转录因子NF-κB细胞核内调控新机制 7月16日，《细胞生物学》杂志发表了我国科学家关于NF-κB信号通路调控的最新研究成果。中国科学院上海生命科学研究院生物化学与细胞生物学研究所王琛研究组新发现了一种名叫UXT的蛋白，它能够在细胞核内与NF-κB转录因子发生相互作用，调节NF-κB在转录增强子上(Enhancer)的功能。NF-κB是免疫应答、炎症反应和机体发育过程中的关键转录因子，它在细胞中的定位与活力受到严格的调控。如果这些调节
http://www.bioon.com 生 物 谷 网 站  生物谷：7月16日，《细胞生物学》杂志发表了我国科学家关于NF-κB信号通路调控的最新研究成果。中国科学院上海生命科学研究院生物化学与细胞生物学研究所王琛研究组新发现了一种名叫UXT的蛋白，它能够在细胞核内与NF-κB转录因子发生相互作用，调节NF-κB在转录增强子上(Enhancer)的功能。

  NF-κB是免疫应答、炎症反应和机体发育过程中的关键转录因子，它在细胞中的定位与活力受到严格的调控。如果这些调节发生异常，就会导致微生物侵染、自身免疫疾病，发育异常和肿瘤等病理现象。NF-κB转录因子通常以非活性形式存在于细胞质中，特定的刺激可诱导其从细胞质转运到细胞核内。过去的研究主要关注各种刺激如何通过复杂的信号转导通路降解细胞质中的NF-κB抑制蛋白。近年的研究表明，NF-κB在细胞核内也受到复杂的调节，影响其转录活力的强度、持续性和特异性。

  王琛研究组发现，UXT是一个新的转录增强子辅助蛋白，能够与NF-κB发生相互作用并调节它的活性。进一步的研究表明：UXT主要促进NF-κB驻留在细胞核内，帮助形成并稳定转录起始复合物。许多肿瘤细胞中NF-κB会异常激活，UXT蛋白的高表达与这种异常变化相关。如果在肿瘤细胞中基因沉默UXT，能够显著削弱NF-κB的活性。该研究揭示了一种在细胞核内调节NF-κB的新层面和新机制，有望成为炎症药物研发的新靶点。

  该项工作是在王琛研究员指导下，由孙绍刚、唐玉杰等人完成。该项目得到科技部“973”和“863”计划、国家自然科学基金委、中国科学院的资助。（上海生命科学研究院）

原始出处:

Published online 9 July 2007
doi:10.1083/jcb.200611081
The Journal of Cell Biology, Vol. 178, No. 2, 231-244

UXT is a novel and essential cofactor in the NF-B transcriptional enhanCEOsome

Shaogang Sun1,2, Yujie Tang1,2, Xiwen Lou1,2, Lianhui Zhu1, Kai Yang1,2, Bianhong Zhang1,2, Hexin Shi1,2, and Chen Wang1

1 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and 2 Graduate University of Chinese Academy of Sciences, Shanghai 200031, China

Correspondence to Chen Wang: cwang01@sibs.ac.cn

As a latent transcription factor, nuclear factor B (NF-B) translocates from the cytoplasm into the nucleus upon stimulation and mediates the expression of genes that are important in immunity, inflammation, and development. However, little is known about how it is regulated inside the nucleus. By a two-hybrid approach, we identify a prefoldin-like protein, ubiquitously expressed transcript (UXT), that is expressed predominantly and interacts specifically with NF-B inside the nucleus. RNA interference knockdown of UXT leads to impaired NF-B activity and dramatically attenuates the expression of NF-B–dependent genes. This interference also sensitizes cells to apoptosis by tumor necrosis factor-. Furthermore, UXT forms a dynamic complex with NF-B and is recruited to the NF-B enhanCEOsome upon stimulation. Interestingly, the UXT protein level correlates with constitutive NF-B activity in human prostate cancer cell lines. The presence of NF-B within the nucleus of stimulated or constitutively active cells is considerably diminished with decreased endogenous UXT levels. Our results reveal that UXT is an integral component of the NF-B enhanCEOsome and is essential for its nuclear function, which uncovers a new mechanism of NF-B regulation.

S. Sun and Y. Tang contributed equally to this paper.

Abbreviations used in this paper: CARM1, coactivator-associated arginine methyltransferase 1; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; EMSA, electrophoretic mobility shift assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IKK, I -B kinase; IL, interleukin; LMB, leptomycin B; NF-B, nuclear factor B; PFD, prefoldin; RHD, Rel homology domain; SR, super repressor; UXT, ubiquitously expressed transcript.