DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

被引:2204
作者
Bartkova, J
Horejsi, Z
Koed, K
Krämer, A
Tort, F
Zieger, K
Guldberg, P
Sehested, M
Nesland, JM
Lukas, C
Orntoft, T
Lukas, J
Bartek, J
机构
[1] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen, Denmark
[2] Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark
[3] Aarhus Univ Hosp, Dept Clin Biochem, DK-8200 Aarhus, Denmark
[4] Univ Copenhagen Hosp, Dept Pathol, DK-2100 Copenhagen, Denmark
[5] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway
[6] Acad Sci Czech Republ, Inst Genet Mol, CZ-16637 Prague, Czech Republic
关键词
D O I
10.1038/nature03482
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
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter- response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions ( but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis ( before genomic instability and malignant conversion), human cells activate an ATR/ATM- regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM - Chk2 p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.
引用
收藏
页码:864 / 870
页数:7
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