Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas

被引：208

作者：

Squatrito, Massimo ^{[1
,2
]}

Brennan, Cameron W. ^{[2
,3
,4
]}

Helmy, Karim ^{[1
,2
]}

Huse, Jason T. ^{[2
,5
]}

Petrini, John H. ^{[6
]}

Holland, Eric C. ^{[1
,2
,4
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol Pathol Program, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Surg Neurosurg, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Mol Biol, New York, NY 10021 USA

来源：

CANCER CELL | 2010年 / 18卷 / 06期

关键词：

DNA-DAMAGE RESPONSE; INTEGRATED GENOMIC ANALYSIS; ATAXIA-TELANGIECTASIA; CONSTITUTIVE ACTIVATION; CANCER SUSCEPTIBILITY; CELLULAR-RESPONSE; STEM-CELLS; ATM; CHK2; CHECKPOINT;

D O I：

10.1016/j.ccr.2010.10.034

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：619 / 629

页数：11

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