Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage.
Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage.
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DOI：
10.1093/toxsci/kfs134
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Pestka JJ
中科院分区：
文献类型：
--
作者：
He K;Zhou HR;Pestka JJ
霉菌毒素脱氧雪腐镰刀菌烯醇（DON）是一种已知的翻译抑制剂，可诱导核糖体RNA （rRNA）切割。在这里，我们将这一过程与(1)特定的18S和28S核糖体RNA切割位点和(2)该途径中特定上游信号元件的身份进行了表征。毛细管电泳结果显示，低浓度浓度为200 ng/ml的DON在6 h后诱导rRNA选择性断裂，浓度为1000 ng/ml的DON在2 h内诱导断裂。Northern blot分析显示，DON暴露诱导28S rRNA的6个片段和18S rRNA的5个片段发生断裂。当使用选择性激酶抑制剂来识别潜在的上游信号时，发现rna激活蛋白激酶（PKR）、造血细胞激酶（Hck）和p38是rRNA切割所必需的，而c-Jun n端激酶和细胞外信号调节激酶则不是。此外，p53抑制剂聚氟乙烯酯-α和聚氟乙烯酯-μ以及半胱天冬酶抑制剂Z-VAD-FMK均能抑制rRNA的断裂。吖啶橙/溴化乙啶染色及流式细胞术证实细胞同时凋亡。DON激活了caspase 3、8和9，这表明在rRNA切割过程中可能存在外源性和内源性凋亡途径的共同参与。satatoxin G （SG）、大霉素（anisomycin）和蓖麻毒素（ricin）也能诱导与DON相同的特异性rRNA切割，这表明核糖素毒素可能共享一个保守的rRNA切割机制。综上所述，don诱导的rRNA切割可能与细胞凋亡激活密切相关，并可能涉及PKR/Hck→p38→p53→caspase 8/9→caspase 3的顺序激活。
The trichothecene mycotoxin deoxynivalenol (DON), a known translational inhibitor, induces ribosomal RNA (rRNA) cleavage. Here, we characterized this process relative to (1) specific 18S and 28S ribosomal RNA cleavage sites and (2) identity of specific upstream signaling elements in this pathway. Capillary electrophoresis indicated that DON at concentrations as low as 200 ng/ml evoked selective rRNA cleavage after 6 h and that 1000 ng/ml caused cleavage within 2 h. Northern blot analysis revealed that DON exposure induced six rRNA cleavage fragments from 28S rRNA and five fragments from 18S rRNA. When selective kinase inhibitors were used to identify potential upstream signals, RNA-activated protein kinase (PKR), hematopoietic cell kinase (Hck), and p38 were found to be required for rRNA cleavage, whereas c-Jun N-terminal kinase and extracellular signal-regulated kinase were not. Furthermore, rRNA fragmentation was suppressed by the p53 inhibitors pifithrin-α and pifithrin-μ as well as the pan caspase inhibitor Z-VAD-FMK. Concurrent apoptosis was confirmed by acridine orange/ethidium bromide staining and flow cytometry. DON activated caspases 3, 8, and 9, thus suggesting the possible coinvolvement of both extrinsic and intrinsic apoptotic pathways in rRNA cleavage. Satratoxin G (SG), anisomycin, and ricin also induced specific rRNA cleavage profiles identical to those of DON, suggesting that ribotoxins might share a conserved rRNA cleavage mechanism. Taken together, DON-induced rRNA cleavage is likely to be closely linked to apoptosis activation and appears to involve the sequential activation of PKR/Hck →p38→p53→caspase 8/9→caspase 3.
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DOI：
10.1084/jem.20020873
发表时间：
2002-09-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ernst M;Inglese M;Scholz GM;Harder KW;Clay FJ;Bozinovski S;Waring P;Darwiche R;Kay T;Sly P;Collins R;Turner D;Hibbs ML;Anderson GP;Dunn AR
通讯作者：
Dunn AR
影响因子：
11.4
作者：
Bulavin, DV;Saito, S;Fornace, AJ
通讯作者：
Fornace, AJ
影响因子：
3.5
作者：
HOUGE, G;DOSKELAND, SO;LANOTTE, M
通讯作者：
LANOTTE, M
DOI：
10.1080/19440049.2010.551301
发表时间：
2012-01-01
影响因子：
2.9
作者：
Hepworth, S. J.;Hardie, L. J.;Turner, P. C.
通讯作者：
Turner, P. C.
影响因子：
3.8
作者：
Chung, YJ;Zhou, HR;Pestka, JJ
通讯作者：
Pestka, JJ