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PMID: 21156285 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas.

Cancer cell ·Vol. 18 ·No. 6 ·2010-12-14 ·Pages 619-29

Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC

Abstract

Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response (DDR) machinery are linked to numerous pathologies including cancer. Here, we present evidence that the DDR exerts tumor suppressor activity in gliomas. We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model. We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment. Finally, we observed that the DDR is constitutively activated in a subset of human GBMs, and such activation correlates with regions of hypoxia.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Cell Cycle Proteins/physiology Cell Hypoxia Cell Line, Tumor Checkpoint Kinase 2 DNA Damage DNA-Binding Proteins/physiology Glioma/etiology,radiotherapy Humans Mice Protein Serine-Threonine Kinases/physiology Radiation Tolerance Signal Transduction/physiology Tumor Suppressor Protein p53/physiology Tumor Suppressor Proteins/physiology
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Tumor Suppressor Protein p53 Tumor Suppressor Proteins Checkpoint Kinase 2 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse CHEK2 protein, human Chek2 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Squatrito Massimo
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Brennan Cameron W
Helmy Karim
Huse Jason T
Petrini John H
Holland Eric C
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2010.10.034
Published
2010-12-14
Pages
619-29
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3818087
Subset
IM
Grants
NCI NIH HHS · U01 CA105492 · United States
NCI NIH HHS · R13 CA162528 · United States
NCI NIH HHS · R01 CA100688 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · U54 CA163167 · United States
NCI NIH HHS · U01 CA141502 · United States
NIGMS NIH HHS · R37 GM059413 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2010.10.034 PMC Full Text View journal details
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