Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf/SKN-1 and p53/CEP-1
Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf/SKN-1 and p53/CEP-1
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DOI：
10.1016/j.freeradbiomed.2011.12.009
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发表时间：
2012-03-01
影响因子：
7.4
通讯作者：
Choe, Keith P.
中科院分区：
文献类型：
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作者：
Leung, Chi K.;Empinado, Hyacinth;Choe, Keith P.
最近，核仁通过调节肿瘤抑制因子p53而成为细胞应激反应的主要协调者。然而，尚不清楚核仁是否调节帽和领（CnC）转录因子SKN-1和Nrf 2，其激活C中保守的抗氧化和解毒反应。elegans和mammals哺乳动物，either分别.筛选出C. elegans鉴定了包含保守的WD 40重复序列的蛋白质WDR-46。该蛋白与酵母UTP 7高度保守，其在18 S rRNA加工和40 S小核糖体亚基的组装中起作用。WDR-46在C.它是rRNA加工所必需的。WDR-46的突变或沉默激活单个C.线虫CnC同源物SKN-1，并增加其靶基因的表达。wdr-46的消耗会降低寿命和抗应激能力，SKN-1可以部分补偿。最后，C.当wdr-46或其它核糖体加工基因沉默时，而不是当翻译起始基因沉默时，线虫p53同源物CEP-1是GST-4激活所部分需要的，这表明核仁功能的破坏可以通过涉及p53/CEP-1的机制激活SKN-1，并且不依赖于蛋白质翻译。(C)2011 Elsevier Inc. All rights reserved.
The nucleolus has recently emerged as a major coordinator of cellular stress responses by regulating the tumor suppressor p53. However, it is not known if the nucleolus regulates the cap 'n' collar (CnC) transcription factors SKN-1 and Nrf2, which activate conserved antioxidant and detoxification responses in C. elegans and mammals, respectively. A screen for negative regulators of detoxification genes in C. elegans identified the conserved WD40 repeat containing protein WDR-46. This protein is highly conserved with yeast UTP7, which functions in 18S rRNA processing and assembly of the 40S small ribosomal subunit. WDR-46 is expressed in the nucleoli of multiple tissues in C. elegans and is required for rRNA processing. Mutation or silencing of WDR-46 activates the single C. elegans CnC homologue SKN-1 and increases expression of its target genes. Depletion of wdr-46 reduces lifespan and stress resistance and SKN-1 partially compensates. Lastly, the C. elegans p53 homologue CEP-1 is partially required for activation of gst-4 when wdr-46 or other ribosome processing genes are silenced but not when translation initiation genes are silenced suggesting that disruptions to nucleolar function can activate SKN-1 by a mechanism that involves p53/cep-1 and is independent of protein translation. (C) 2011 Elsevier Inc. All rights reserved.