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

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. He...

Full description

Saved in:

Bibliographic Details
Published in:	Nature Vol. 434; no. 7035; pp. 864 - 870
Main Authors:	Bartkova, Jirina, Ørntoft, Torben, Lukas, Jiri, Ho ejší, Zuzana, Nesland, Jahn M, Lukas, Claudia, Guldberg, Per, Krämer, Alwin, Tort, Frederic, Sehested, Maxwell, Koed, Karen, Bartek, Jiri, Zieger, Karsten
Format:	Journal Article
Language:	English
Published:	London Nature Publishing 14-04-2005 Nature Publishing Group
Subjects:	Allelic Imbalance - genetics Biological and medical sciences Cancer Carcinogenesis, carcinogens and anticarcinogens cdc25 Phosphatases - genetics cdc25 Phosphatases - metabolism Cell Cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell division Cell Line, Tumor Cell Transformation, Neoplastic - genetics Checkpoint Kinase 2 Cyclin E - genetics Cyclin E - metabolism Deoxyribonucleic acid DNA DNA Damage - genetics DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism E2F Transcription Factors Enzyme Activation Gene expression General aspects Genes, p53 - genetics Genomic Instability Genomics Humans Medical sciences Mutation - genetics Neoplasms - enzymology Neoplasms - genetics Neoplasms - pathology Neoplasms - prevention & control Oncogenes - genetics Oncogenes - physiology Phosphorylation Polymorphism, Single Nucleotide - genetics Protein-Serine-Threonine Kinases - metabolism Signal Transduction Transcription Factors - genetics Transcription Factors - metabolism Tumors Urinary bladder Urinary Bladder Neoplasms - enzymology Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - pathology Human Cancerology DNA Genetics Tumorigenicity Lesion Malignant tumor Carcinogenesis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0028-0836 1476-4687
DOI:	10.1038/nature03482