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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

机译：癌基因诱导的衰老是DNA损伤检查点施加的肿瘤发生屏障的一部分

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摘要

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest(1,2), whereas a second barrier is mediated by oncogene-induced senescence(3-6). The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
机译：最近的研究表明，存在可减慢或抑制肿瘤前发展为瘤形成的肿瘤发生障碍。一种这样的屏障涉及DNA复制应力，其导致DNA损伤检查点的激活，从而导致细胞凋亡或细胞周期停滞（1,2），而第二种屏障是由癌基因诱导的衰老介导的（3-6）。这两个障碍之间的关系（如果有的话）尚未阐明。在这里，我们显示癌基因诱导的衰老与DNA复制压​​力的迹象有关，包括过早终止的DNA复制叉和DNA双链断裂。抑制DNA双链断裂反应激酶共济失调毛细血管扩张突变（ATM）抑制了衰老的诱导，并且在小鼠模型中导致肿瘤大小和侵袭性增加。对人类癌前病变的分析进一步表明，DNA损伤和衰老标记紧密共聚。因此，人肿瘤前病变中的衰老是癌基因诱导的DNA复制压​​力的表现，并且与凋亡一起为恶性进展提供了障碍。

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  • 来源
    《Nature》 |2006年第7119期|p. 633-637|共5页
  • 作者

    Bartkova J; Rezaei N; Liontos M; Karakaidos P; Kletsas D; Issaeva N; Vassiliou LVF; Kolettas E; Niforou K; Zoumpourlis VC;

  • 作者单位

    Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA;

    Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen, Denmark;

    Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark;

    Univ Athens, Sch Med, Dept Histol & Embryol, GR-11527 Athens, Greece;

    Demokritos Natl Ctr Sci Res, Inst Biol, GR-15310 Athens, Greece;

    Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden;

    Univ Ioannina, Sch Med, Dept Physiol, GR-45110 Ioannina, Greece;

    Natl Hellen Res Fdn, Inst Biol Res & Biotechnol, GR-11635 Athens, Greece;

    Univ Penn, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA;

    Univ Copenhagen Hosp, Dept Pathol, DK-2100 Copenhagen, Denmark;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);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 自然科学总论;
  • 关键词

    PREMATURE SENESCENCE; CELLULAR SENESCENCE; HUMAN-CELLS; REPLICATION; ATM; P53; SUPPRESSION; INSTABILITY; P16(INK4A); ACTIVATION;

    机译：早衰;细胞衰老;人细胞;复制;ATM;P53;抑制;不稳定;P16（INK4A）;激活;

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