DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
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DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. / Bartkova, Jirina; Horejsí, Zuzana; Koed, Karen; Krämer, Alwin; Tort, Frederic; Zieger, Karsten; Guldberg, Per; Sehested, Maxwell; Nesland, Jahn M; Lukas, Claudia; Ørntoft, Torben; Lukas, Jiri; Bartek, Jiri.
In: Nature, Vol. 434, No. 7035, 14.04.2005, p. 864-70.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
AU - Bartkova, Jirina
AU - Horejsí, Zuzana
AU - Koed, Karen
AU - Krämer, Alwin
AU - Tort, Frederic
AU - Zieger, Karsten
AU - Guldberg, Per
AU - Sehested, Maxwell
AU - Nesland, Jahn M
AU - Lukas, Claudia
AU - Ørntoft, Torben
AU - Lukas, Jiri
AU - Bartek, Jiri
PY - 2005/4/14
Y1 - 2005/4/14
N2 - 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.
AB - 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.
KW - Allelic Imbalance/genetics
KW - Cell Cycle
KW - Cell Cycle Proteins/genetics
KW - Cell Line, Tumor
KW - Cell Transformation, Neoplastic/genetics
KW - Checkpoint Kinase 2
KW - Cyclin E/genetics
KW - DNA Damage/genetics
KW - DNA-Binding Proteins/genetics
KW - E2F Transcription Factors
KW - Enzyme Activation
KW - Genes, p53/genetics
KW - Genomic Instability
KW - Humans
KW - Mutation/genetics
KW - Neoplasms/enzymology
KW - Oncogenes/genetics
KW - Phosphorylation
KW - Polymorphism, Single Nucleotide/genetics
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Signal Transduction
KW - Transcription Factors/genetics
KW - Urinary Bladder Neoplasms/enzymology
KW - cdc25 Phosphatases/genetics
U2 - 10.1038/nature03482
DO - 10.1038/nature03482
M3 - Journal article
C2 - 15829956
VL - 434
SP - 864
EP - 870
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7035
ER -
ID: 246727912