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首页> 外文期刊>Science Signaling >The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer
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The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer

机译：激酶P38和JNK的核转移促进炎症癌症

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摘要

The stimulated nuclear translocation of signaling proteins, such as MAPKs, is a necessity for the initiation and regulation of their physiological functions. Previously, we determined that nuclear translocation of the MAPKs p38 and JNK involves binding to heterodimers comprising importin 3 and either importin 7 or importin 9. Here, we identified the importin-binding region in p38 and JNK and developed a myristoylated peptide targeting this site that we called PERY. The PERY peptide specifically blocked the interaction of p38 and JNK with the importins, restricted their nuclear translocation, and inhibited phosphorylation of their nuclear (but not cytoplasmic) substrates. Through these effects, the PERY peptide reduced the proliferation of several (but not all) cancer cell lines in culture and inhibited the growth of a human breast cancer xenograft in mice. In addition, the PERY peptide substantially inhibited inflammation in mice, as manifested in models of colitis and colitis-associated colon cancer. The PERY peptide more effectively prevented colon cancer development than did a commercial p38 inhibitor. In vivo analysis further suggested that this effect was mediated by PERY peptide-induced prevention of the nuclear translocation of p38 in macrophages. Together, these results support the use of the nuclear translocation of p38 and JNK as a novel drug target to treat various cancers and inflammation-induced diseases.
机译：信号传导蛋白（例如MAPK）的刺激的核转位是对其生理功能引发和调节的必要性。以前，我们确定麦克马克人P38和JNK的核易位涉及与包含衍生素3和Importin 7或Importin 9的异二聚体的结合。在此，我们在P38和JNK中鉴定了Importin结合区域，并开发了靶向该网站的肌苷肽肽。我们打电话给ery。 PERY肽特异性地阻断了P38和JNK与IMPRESINS的相互作用，限制了它们的核易位，并抑制它们的核（但不是细胞质）基材的磷酸化。通过这些效果，腹部肽降低了培养中的几种（但不是全部）癌细胞系的增殖，并抑制了小鼠中人乳腺癌异种移植物的生长。此外，腹部肽在小鼠中显着抑制炎症，如表结肠炎和结肠炎相关的结肠癌模型中。腹部肽更有效地预防结肠癌的开发，而不是商业P38抑制剂。体内分析进一步表明，这种效果是通过百分之肽诱导的预防巨噬细胞核易位的核转位介导的。这些结果在一起，支持使用P38和JNK的核转移作为一种新药，治疗各种癌症和炎症诱导的疾病。

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  • 来源
    《Science Signaling》 |2018年第525期|共15页
  • 作者

    Maik-Rachline Galia; Zehorai Elder; Hanoch Tamar; Blenis John; Seger Rony;

  • 作者单位

    Weizmann Inst Sci Dept Biol Regulat IL-76100 Rehovot Israel;

    Weizmann Inst Sci Dept Biol Regulat IL-76100 Rehovot Israel;

    Weizmann Inst Sci Dept Biol Regulat IL-76100 Rehovot Israel;

    Weill Cornell Med New York NY 10021 USA;

    Weizmann Inst Sci Dept Biol Regulat IL-76100 Rehovot Israel;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
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