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

被引:1526
作者
Bartkova, Jirina
Rezaei, Nousin
Liontos, Michalis
Karakaidos, Panagiotis
Kletsas, Dimitris
Issaeva, Natalia
Vassiliou, Leandros-Vassilios F.
Kolettas, Evangelos
Niforou, Katerina
Zoumpourlis, Vassilis C.
Takaoka, Munenori
Nakagawa, Hiroshi
Tort, Frederic
Fugger, Kasper
Johansson, Fredrik
Sehested, Maxwell
Andersen, Claus L.
Dyrskjot, Lars
Orntoft, Torben
Lukas, Jiri
Kittas, Christos
Helleday, Thomas
Halazonetis, Thanos D. [1 ]
Bartek, Jiri
Gorgoulis, Vassilis G.
机构
[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
[2] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen, Denmark
[3] Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark
[4] Univ Athens, Sch Med, Dept Histol & Embryol, GR-11527 Athens, Greece
[5] Demokritos Natl Ctr Sci Res, Inst Biol, GR-15310 Athens, Greece
[6] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden
[7] Univ Ioannina, Sch Med, Dept Physiol, GR-45110 Ioannina, Greece
[8] Natl Hellen Res Fdn, Inst Biol Res & Biotechnol, GR-11635 Athens, Greece
[9] Univ Penn, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA
[10] Univ Copenhagen Hosp, Dept Pathol, DK-2100 Copenhagen, Denmark
[11] Aarhus Univ Hosp, Dept Clin Biochem, DK-8200 Aarhus N, Denmark
[12] Univ Sheffield, Inst Canc Studies, Sheffield S10 2RX, S Yorkshire, England
[13] Univ Geneva, Dept Mol Biol, CH-1211 Geneva 4, Switzerland
关键词
D O I
10.1038/nature05268
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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.
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收藏
页码:633 / 637
页数:5
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