Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon
Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon
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DOI：
10.1089/jir.2004.24.647
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发表时间：
2004-11-01
影响因子：
2.3
通讯作者：
Hassel, BA
中科院分区：
文献类型：
--
作者：
Liu, MJ;Hummer, BT;Hassel, BA
干扰素 (IFN) 刺激基因 (15 kDa) (ISG15) 是一种类泛素蛋白，可与细胞蛋白形成共价缀合物。 ISG15 由 IFN、微生物挑战和 p53 诱导，表明它代表了多种应激刺激所共有的遗传反应。为了研究基因毒性化疗剂对这种翻译后修饰途径的调节，我们检查了用拓扑异构酶 I (topoI) 毒物喜树碱 (CPT) 处理的细胞中 ISG15 的诱导和结合。 CPT 诱导 ISG15 mRNA，诱导需要蛋白质合成和功能性 p53 蛋白。然而，IFN 和 IFN 信号通路的 Jak-Stat 成分对于 ISG15 的 CPT 诱导是可有可无的。 CPT 以剂量依赖性和时间依赖性方式诱导游离 ISG15 和缀合物。单个 55 kDa 蛋白是 CPT 诱导的 ISG15 缀合物，定位于核区室。 CPT 诱导的 ISG15 缀合物与 IFN 诱导的 ISG15 缀合物不同；然而，CPT 治疗显着增强了 ISG15 对 IFN 的反应。这些发现提供了离散 ISG15 缀合物种类的刺激特异性诱导的第一个证据，并证明癌症治疗剂的组合治疗可以协同增强 ISG15 缀合。化疗药物诱导的特定 ISG15 缀合物的鉴定可能会揭示新的分子靶标。
Interferon (IFN)-stimulated gene (15 kDa) (ISG15) is a ubiquitin-like protein that forms covalent conjugates with cellular proteins. ISG15 is induced by IFN, microbial challenge, and p53, suggesting that it represents a genetic response that is shared among diverse stress stimuli. To investigate the regulation of this posttranslational modification pathway by a genotoxic chemotherapeutic agent, we examined ISG15 induction and conjugation in cells treated with the topoisomerase I (topoI) poison, camptothecin (CPT). CPT induced ISG15 mRNA, and induction required protein synthesis and a functional p53 protein. However, IFN and the Jak-Stat components of the IFN signaling pathway were dispensable for CPT induction of ISG15. CPT induced free ISG15 and conjugates in a dose-dependent and time-dependent manner. A single 55-kDa protein was the prominent CPT-induced ISG15 conjugate and localized to the nuclear compartment. CPT-induced ISG15 conjugates were distinct from those induced by IFN; however, CPT treatment dramatically enhanced ISG15 conjugation in response to IFN. These findings provide the first evidence of a stimulus-specific induction of discrete ISG15 conjugate species and demonstrate that treatment with a combination of cancer therapeutic agents can cooperate to enhance ISG15 conjugation. Identification of the specific ISG15 conjugates induced by chemotherapeutic agents may reveal novel molecular targets.