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首页> 外文学位 >RNA polymerase II large subunit degradation induced by ecteinascidin 743: Molecular characterization and subsequent rational investigation of antitumor mechanisms in cancers with clinical response.
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RNA polymerase II large subunit degradation induced by ecteinascidin 743: Molecular characterization and subsequent rational investigation of antitumor mechanisms in cancers with clinical response.

机译：由ecteinascidin 743诱导的RNA聚合酶II大亚基降解：具有临床反应的癌症的分子表征和随后的抗肿瘤机制的合理研究。

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摘要

Ecteinascidin 743 (Et-743), which is a novel DNA minor groove alkylator with a unique spectrum of antitumor activity, is currently being evaluated in phase II/III clinical trials. Although the precise molecular mechanisms responsible for the observed antitumor activity are poorly understood, recent data suggests that post-translational modifications of RNA polymerase II Large Subunit (RNAPII LS) may play a central role in the cellular response to this promising anticancer agent. The stalling of an actively transcribing RNAPII LS at Et-743-DNA adducts is the initial cellular signal for transcription-coupled nucleotide excision repair (TC-NER). In this manner, Et-743 poisons TC-NER and produces DNA single strand breaks. Et-743 also inhibits the transcription and RNAPII LS-mediated expression of selected genes. Because the poisoning of TC-NER and transcription inhibition are critical components of the molecular response to Et-743 treatment, we have investigated if changes in RNAPII LS contribute to the disruption of these two cellular pathways. In addition, we have studied changes in RNAPII LS in two tumors for which clinical responses were reported in phase I/II clinical trials: renal cell carcinoma and Ewing's sarcoma. Our results demonstrate that Et-743 induces degradation of the RNAPII LS that is dependent on active transcription, a functional 26S proteasome, and requires functional TC-NER, but not global genome repair. Additionally, we have provided the first experimental data indicating that degradation of RNAPII LS might lead to the inhibition of activated gene transcription. A set of studies performed in isogenic renal carcinoma cells deficient in von Hippel-Lindau protein, which is a ubiquitin-E3-ligase for RNAPII LS, confirmed the central role of RNAPII LS degradation in the sensitivity to Et-743. Finally, we have shown that RNAPII LS is also degraded in Ewing's sarcoma tumors following Et-743 treatment and provide data to suggest that this event plays a role in decreased expression of the Ewing's sarcoma oncoprotein, EWS-Fli1. Altogether, these data implicate degradation of RNAPII LS as a critical event following Et-743 exposure and suggest that the clinical activity observed in renal carcinoma and Ewing's sarcoma may be mediated by disruption of molecular pathways requiring a fully functional RNAPII LS.
机译：Ecteinascidin 743（Et-743）是一种具有独特抗肿瘤活性谱的新型DNA小沟烷基化剂，目前正在II / III期临床试验中进行评估。尽管对观察到的抗肿瘤活性的精确分子机制了解甚少，但最近的数据表明，RNA聚合酶II大亚基（RNAPII LS）的翻译后修饰可能在细胞对这种有前途的抗癌剂的反应中起核心作用。在Et-743-DNA加合物上活跃转录的RNAPII LS的失速是转录偶联核苷酸切除修复（TC-NER）的初始细胞信号。以这种方式，Et-743使TC-NER中毒并产生DNA单链断裂。 Et-743还抑制所选基因的转录和RNAPII LS介导的表达。因为TC-NER的中毒和转录抑制是对Et-743治疗的分子反应的关键组成部分，所以我们研究了RNAPII LS的改变是否有助于破坏这两个细胞途径。此外，我们已经研究了两种肿瘤的RNAPII LS的变化，这些肿瘤在I / II期临床试验中已报告了临床反应：肾细胞癌和尤因氏肉瘤。我们的研究结果表明，Et-743诱导RNAPII LS的降解，该降解依赖于活性转录（一种功能性26S蛋白酶体），并且需要功能性TC-NER，而不是全局基因组修复。此外，我们提供了第一个实验数据，表明RNAPII LS的降解可能导致激活基因转录的抑制。在缺乏von Hippel-Lindau蛋白的等基因肾癌细胞中进行的一组研究证实了RNAPII LS降解在对Et-743的敏感性中起着核心作用，von Hippel-Lindau蛋白是RNAPII LS的泛素-E3连接酶。最后，我们已经显示，Et-743治疗后，RNAPII LS在尤因氏肉瘤肿瘤中也被降解，并提供数据表明该事件在尤因氏肉瘤癌蛋白EWS-Fli1的表达降低中起作用。总而言之，这些数据暗示RNAPII LS的降解是Et-743暴露后的关键事件，并表明在肾癌和尤因氏肉瘤中观察到的临床活性可能是由需要完全功能的RNAPII LS的分子途径的破坏介导的。

著录项

  • 作者

    Aune, Gregory J.;

  • 作者单位

    The University of Texas Graduate School of Biomedical Sciences at Houston.;

  • 授予单位 The University of Texas Graduate School of Biomedical Sciences at Houston.;
  • 学科 Health Sciences Oncology.; Chemistry Pharmaceutical.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;药物化学;药理学;
  • 关键词

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