TAK1 ubiquitination regulates doxorubicin-induced NF-κB activation.
TAK1 ubiquitination regulates doxorubicin-induced NF-κB activation.
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DOI：
10.1016/j.cellsig.2012.09.003
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发表时间：
2013-01
影响因子：
4.8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Liang L;Fan Y;Cheng J;Cheng D;Zhao Y;Cao B;Ma L;An L;Jia W;Su X;Yang J;Zhang H
化疗药物和放射治疗诱导的癌细胞中NF-κB活化有助于肿瘤侵袭性生长以及癌症治疗期间对化疗和电离辐射的抗性。TAK 1已被证明是遗传毒性应激诱导的NF-κB活化所必需的。然而，TAK 1泛素化是否参与了遗传毒性应激诱导的NF-κB活化仍不清楚。在此，我们证明TAK 1泛素化在阿霉素（Dox）诱导的NF-κB活化的正性和负性调节中起重要作用。我们发现TAK 1是Dox诱导的NF-κB活化所必需的。在Dox处理的早期阶段，Dox诱导Lys 63连接的TAK 1在赖氨酸158残基处的多聚泛素化。USP 4抑制Dox诱导的TAK 1 Lys 63连接的多聚泛素化，并且USP 4的敲低增强Dox诱导的NF-κB活化。在Dox处理的后期，Dox诱导Lys 48连接的TAK 1多聚泛素化以促进TAK 1降解。ITCH通过促进Lys 48连接的TAK 1多聚泛素化及其随后的降解来抑制Dox诱导的NF-κB活化。我们的研究表明TAK 1泛素化在Dox诱导的NF-κB活化的调节中起着关键作用。因此，干预TAK 1激酶活性或TAK 1 Lys 63连接的多聚泛素化途径可能会大大增强Dox的治疗效果。
Chemotherapeutic agents- and radiation therapy-induced NF-κB activation in cancer cells contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. TAK1 has been shown to be required for genotoxic stress-induced NF-κB activation. However, whether TAK1 ubiquitination is involved in genotoxic stress-induced NF-κB activation remains unknown. Herein, we demonstrate that TAK1 ubiquitination plays an important role in the positive and negative regulation of Doxorubicin (Dox)-induced NF-κB activation. We found that TAK1 was required for Dox-induced NF-κB activation. At the early stage of Dox treatment, Dox induced Lys63-linked TAK1 polyubiquitination at lysine 158 residue. USP4 inhibited Dox-induced TAK1 Lys63-linked polyubiquitination and knockdown of USP4 enhanced Dox-induced NF-κB activation. At the late stage of Dox treatment, Dox induced Lys48-linked TAK1 polyubiquitination to promote TAK1 degradation. ITCH inhibited Dox-induced NF-κB activation by promoting Lys48-linked TAK1 polyubiquitination and its subsequent degradation. Our study indicates that TAK1 ubiquitination plays critical roles in the regulation of Dox-induced NF-κB activation. Thus, intervention of TAK1 kinase activity or TAK1 Lys63-linked polyubiquitination pathways might greatly enhance the therapeutic efficacy of Dox.
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通过PARP-1，需要通过PARP-1进行反馈调节的聚（ADP-核糖基），才能快速响应活细胞中的DNA损伤。
影响因子：
14.9
作者：
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发表时间：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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