...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia
【24h】

Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia

机译：Notch信号有助于人类T细胞白血病病毒1型相关成人T细胞白血病的增殖和肿瘤形成

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The Notch signaling pathway plays an important role in cellular proliferation, differentiation, and apoptosis. Unregulated activation of Notch signaling can result in excessive cellular proliferation and cancer. Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). The disease has a dismal prognosis and is invariably fatal. In this study, we report a high frequency of constitutively activated Notch in ATL patients. We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. Compared with the exclusive activating frameshift mutations in the proline, glutamic acid, serine, and threonine (PEST) domain in T-ALLs, those in ATLs have, in addition, single-substitution mutations in this domain leading to reduced CDC4/Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch 1 (ICN1). Finally, we demonstrated that inhibition of Notch signaling by γ-secretase inhibitors reduced tumor cell proliferation and tumor formation in ATL-engrafted mice. These data suggest that activated Notch may be important to ATL pathogenesis and reveal Notch 1 as a target for therapeutic intervention in ATL patients.
机译：Notch信号通路在细胞增殖，分化和凋亡中起重要作用。 Notch信号的不受调节的激活可能导致过度的细胞增殖和癌症。 1型人类T细胞白血病病毒（HTLV-1）是成人T细胞白血病（ATL）的病原体。这种疾病的预后很差，而且总是致命的。在这项研究中，我们报告了ATL患者中高频率的组成性激活Notch。在超过30％的ATL患者中，我们发现Notch中的激活突变。这些活化突变与以前在T-ALL白血病中报道的突变在表型上有所不同，并且可能代表人类癌症中活化的Notch的多态性。与T-ALLs中脯氨酸，谷氨酸，丝氨酸和苏氨酸（PEST）域中的排他性激活移码突变相比，ATL中的ATL具有单取代突变，导致CDC4 / Fbw7介导的减少降解和Notch 1（ICN1）的细胞内切割形式的稳定化。最后，我们证明了γ-分泌酶抑制剂对Notch信号的抑制作用会降低ATL移植小鼠的肿瘤细胞增殖和肿瘤形成。这些数据表明，激活的Notch对ATL发病机理可能很重要，并揭示了Notch 1作为ATL患者治疗干预的靶标。

著录项

  • 来源
  • 作者

    Joanna Pancewicz; John M. Taylor; Abhik Datta; Hicham H. Baydoun; Thomas A. Waldmann; Olivier Hermine; Christophe Nicot;

  • 作者单位

    Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;

    rnDepartment of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;

    rnDepartment of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;

    rnDepartment of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;

    rnMetabolism Branch, National Institutes of Health, Bethesda, MD 20892;

    rnUnite Mixte de Recherche 8603, Necker Hospital, Centre National de la Recherche Scientifique, 75743 Paris Cedex 15, France;

    rnDepartment of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号