NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression.
NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression.
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DOI：
10.18632/oncotarget.1643
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发表时间：
2014-01-30
期刊：
影响因子：
--
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Huang H;Ma L;Li J;Yu Y;Zhang D;Wei J;Jin H;Xu D;Gao J;Huang C
NF-κB是一种已知的转录因子，参与多种基因转录和生物学过程的调控，其中大多数依赖于p65/RelA亚基的转录活性，而另一种广泛表达的亚基NF-κB1（p50）由于缺乏转录激活结构域，其生物学功能尚不清楚。在此，我们发现了一种新的生物学功能，即p50作为砷处理后致癌c-Myc蛋白降解的调节剂，其机制与NF-κB转录无关。我们的研究结果发现，p50是至关重要的c-Myc蛋白诱导砷处理后，通过使用特定的敲低和缺失的p50在其正常表达的细胞，以及重建表达的p50在其缺陷的细胞。随后，我们发现p50主要通过抑制c-Myc蛋白的降解来上调c-Myc蛋白的表达。我们还发现，p50通过抑制FBW 7表达表现出这种新的特性。与p50完整细胞相比，p50缺陷细胞中的FBW 7显著上调，而p50-/-细胞中的FBW 7敲低恢复了亚砷酸盐诱导的c-Myc蛋白积累，确保FBW 7上调是p50-/-细胞中c-Myc蛋白表达缺陷的原因。另外，我们发现p50通过抑制转录因子E2 F1的反式激活而抑制fbw 7基因的转录。总的来说，我们的研究证明了p50作为c-Myc蛋白降解的调节剂的新功能，有助于我们的概念，即p50通过蛋白质翻译和降解的多个水平调节蛋白质表达，进一步提供了对p50蛋白生物医学意义的理解的重要见解。
NF-κB is a well-known transcription factor in regulation of multiple gene transcription and biological processes, and most of them are relied on its transcriptional activity of the p65/RelA subunit, while biological function of another ubiquitously expressed subunit NF-κB1 (p50) remains largely unknown due to lack transcriptional activation domain. Here we discovered a novel biological function of p50 as a regulator of oncogenic c-Myc protein degradation upon arsenite treatment in a NF-κB transcriptional-independent mechanism. Our results found that p50 was crucial for c-Myc protein induction following arsenite treatment by using specific knockdown and deletion of p50 in its normal expressed cells as well as reconstituting expression of p50 in its deficient cells. Subsequently we showed that p50 upregulated c-Myc protein expression mainly through inhibiting its degradation. We also identified that p50 exhibited this novel property by suppression of FBW7 expression. FBW7 was profoundly upregulated in p50-defecient cells in comparison to that in p50 intact cells, whereas knockdown of FBW7 in p50-/- cells restored arsenite-induced c-Myc protein accumulation, assuring that FBW7 up-regulation was responsible for defect of c-Myc protein expression in p50-/- cells. In addition, we discovered that p50 suppressed fbw7 gene transcription via inhibiting transcription factor E2F1 transactivation. Collectively, our studies demonstrated a novel function of p50 as a regulator of c-Myc protein degradation, contributing to our notion that p50-regulated protein expression through multiple levels at protein translation and degradation, further providing a significant insight into the understanding of biomedical significance of p50 protein.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
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Wei, Wenyi
影响因子：
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作者：
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通讯作者：
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影响因子：
25
作者：
Hoeck, Joerg D.;Jandke, Anett;Behrens, Axel
通讯作者：
Behrens, Axel
影响因子：
10.4
作者：
Ouyang W;Luo W;Zhang D;Jian J;Ma Q;Li J;Shi X;Chen J;Gao J;Huang C
通讯作者：
Huang C
DOI：
10.1016/j.bbamcr.2013.04.012
发表时间：
2013-09
影响因子：
5.1
作者：
Che, Xun;Liu, Jinyi;Huang, Haishan;Mi, Xiaoyi;Xia, Qing;Li, Jingxia;Zhang, Dongyun;Ke, Qingdong;Gao, Jimin;Huang, Chuanshu
通讯作者：
Huang, Chuanshu