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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis
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Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis

机译：昼夜节律性破坏可通过p73介导的细胞凋亡提高化疗效果

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摘要

The circadian clock in mammalian organisms is generated by a transcription-translation feedback loop that controls many biochemical pathways at the cellular level and physiology and behavior at the organismal level. Cryptochrome (Cry) is a key protein in the negative arm of the transcription-translation feedback loop. It has been found that Cry mutation in cells with p53-null genotype increased their sensitivity to apoptosis by genotoxic agents. Here we show that this increased sensitivity is due to up-regulation of the p53 gene family member p73 in response to DNA damage. As a consequence, when tumors arising from oncogenic Ras-transformed p53~(-/-) and p53~(-/-)Cry1~(-/-)Cry2~(-/-) cells are treated with the antican-cer drug oxaliplatin, p53~(-/-) tumors continue to grow whereas p53~(-/-)Cry1~(-/-)Cry2~(-/-) tumors exhibit extensive apoptosis and stop growing. This finding provides a mechanistic foundation for overcoming the resistance of p53-deficient tumor cells to apoptosis induced by DNA-damaging agents and suggests that disruption of cryptochrome function may increase the sensitivity of tumors with p53 mutation to chemotherapy.
机译：哺乳动物生物体的生物钟由转录-翻译反馈环产生，该环在细胞水平控制许多生化途径，在生物水平控制生理和行为。隐铬蛋白（Crychrome，Crychrome）是转录-翻译反馈环负端的关键蛋白。已经发现，具有p53无效基因型的细胞中的Cry突变增加了其对遗传毒性剂对细胞凋亡的敏感性。在这里我们表明，这种增加的敏感性是由于p53基因家族成员p73响应DNA损伤而上调的。结果，当用致癌Ras转化的p53〜（-/-）和p53〜（-/-）Cry1〜（-/-）Cry2〜（-/-）细胞引起的肿瘤用抗癌药治疗时奥沙利铂，p53〜（-/-）肿瘤继续生长，而p53〜（-/-）Cry1〜（-/-）Cry2〜（-/-）肿瘤表现出广泛的细胞凋亡并停止生长。这一发现为克服p53缺陷型肿瘤细胞对DNA损伤剂诱导的细胞凋亡的抗性提供了机制基础，并暗示了隐色功能的破坏可能会增加具有p53突变的肿瘤对化学疗法的敏感性。

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    Jin Hyup Lee; Aziz Sancar;

  • 作者单位

    Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599;

    Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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