Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway.
Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway.
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DOI：
10.1093/nar/gky455
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发表时间：
2018-07-06
影响因子：
14.9
通讯作者：
Stark LA
中科院分区：
文献类型：
--
作者：
Chen J;Lobb IT;Morin P;Novo SM;Simpson J;Kennerknecht K;von Kriegsheim A;Batchelor EE;Oakley F;Stark LA
p53作为核仁应激的效应子是明确的，但p53独立的机制在很大程度上是未知的。与p53一样，NF-κ B转录因子在维持应激下的细胞内稳态中起关键作用。许多刺激NF-κ B的应激也会破坏核仁。然而，核仁功能和NF-κ B通路激活之间的联系尚不清楚。在这里，我们证明了人工破坏PolI复合物刺激NF-κ B信号。与p53核仁应激反应不同，这种效应似乎与rDNA转录的抑制无关。我们发现NF-κ B的特异性应激刺激诱导PolI复合物的关键组分TIF-IA降解。这种降解先于NF-κ B的活化，并与核仁大小增加有关。它被CDK4抑制所模拟，并依赖于一种涉及UBF/p14 ARF和蛋白质S44的新途径。我们发现阻断TIF-IA降解阻断了应激对核仁大小和NF-κ B信号传导的影响。最后，使用离体培养，我们证明了在暴露于化学预防剂阿司匹林的新鲜切除的人类结直肠肿瘤中，TIF-IA的降解和NF-κ B的活化之间存在强相关性。总之，我们的研究提供了令人信服的证据，一个新的，TIF-IA-NF-κ B核仁应激反应途径，具有体内相关性和治疗意义。
p53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that artificial disruption of the PolI complex stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of NF-κB and is associated with increased nucleolar size. It is mimicked by CDK4 inhibition and is dependent upon a novel pathway involving UBF/p14ARF and S44 of the protein. We show that blocking TIF-IA degradation blocks stress effects on nucleolar size and NF-κB signalling. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, TIF-IA–NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.
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影响因子：
--
作者：
Esposito D;Crescenzi E;Sagar V;Loreni F;Russo A;Russo G
通讯作者：
Russo G
影响因子：
4.8
作者：
Charruyer, A;Grazide, S;Jaffrezou, JP
通讯作者：
Jaffrezou, JP
DOI：
10.4161/nucl.32235
发表时间：
2014-09
期刊：
Nucleus (Austin, Tex.)
影响因子：
--
作者：
James A;Wang Y;Raje H;Rosby R;DiMario P
通讯作者：
DiMario P
影响因子：
8
作者：
Ayrault, O;Andrique, L;Seite, P
通讯作者：
Seite, P
影响因子：
56.9
作者：
KOPP, E;GHOSH, S
通讯作者：
GHOSH, S