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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model
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Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

机译:异位Myc目标基因JAG2的诱导增强人B细胞模型中的低氧生长和肿瘤发生

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摘要

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.
机译:异位Myc表达在人类肿瘤发生中起关键作用,在转基因小鼠中已经很好地建立了Myc剂量依赖性肿瘤发生,但是还没有很好地表征依赖于Myc水平的Myc靶基因。在这方面,我们使用了人类P493-6 B细胞(其具有依赖于Epstein-Barr病毒EBNA2蛋白的肿瘤前状态和具有异位诱导型Myc的肿瘤状态)来鉴定假定的异位Myc目标基因。在异位靶标中,编码Notch受体配体Jagged2的JAG2由Myc直接诱导。通过靶向JAG2或γ-分泌酶的Notch抑制剂N- [N-(3,5-二氟苯乙酰基)-L-丙氨酰]-(S)-苯基甘氨酸叔丁酯(DAPT)抑制Notch信号传导优先抑制了肿瘤状态体外。此外,体内DAPT抑制了P493-6的肿瘤发生。 JAG2的异位表达没有增强需氧细胞的增殖,但在体外增加了缺氧细胞的增殖,并显着增加了体内肿瘤发生。此外,Jagged2在P493-6肿瘤中的表达通常与缺氧区域重叠。这些观察结果表明,Myc下游的Notch信号传导使细胞能够适应低氧的肿瘤微环境。

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  • 作者单位

    Departments of Pediatrics, Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Departments of Pathology,Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Departments of Medicine,Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Departments of Microarray Facility, Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Departments of Medicine,Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Departments of Pathology,Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ 85259 Department of Medicine, Yong Loo Lin School of Medicine,National University of Singapore, Singapore 545523;

    Departments of Pathology,Johns Hopkins University School of Medicine,Baltimore, MD 21205;

    Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ 85259;

    Departments of Pathology,Johns Hopkins University School of Medicine,Baltimore, MD 21205 Departments of Medicine,Johns Hopkins University School of Medicine,Baltimore, MD 21205 Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine,Baltimore, MD 21205;

  • 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

    neoplasia; notch; target genes; transcription; hypoxia;

    机译:肿瘤缺口;靶基因转录缺氧;

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