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

   

Authors:	Squatrito, M.; Brennan, C. W.; Helmy, K.; Huse, J. T.; Petrini, J. H.; Holland, E. C.
Article Title:	Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas
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. © 2010 Elsevier Inc.
Keywords:	immunohistochemistry; signal transduction; clinical article; controlled study; human tissue; dna-binding proteins; nonhuman; radiation dose; glioma; antineoplastic agent; mouse; animals; cell cycle proteins; mice; dna damage; cell cycle; animal experiment; animal model; in vivo study; neural stem cell; in vitro study; cell line, tumor; wild type; protein p53; carcinogenesis; hypoxia; protein-serine-threonine kinases; glioblastoma; tumor suppressor proteins; atm protein; ionizing radiation; tumor suppressor protein p53; radiosensitivity; checkpoint kinase 2; cell hypoxia; genetic code; radiation tolerance
Journal Title:	Cancer Cell
Volume:	18
Issue:	6
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2010-12-14
Start Page:	619
End Page:	629
Language:	English
DOI:	10.1016/j.ccr.2010.10.034
PUBMED:	21156285
PROVIDER:	scopus
PMCID:	PMC3818087
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-78650014447&partnerID=40&md5=f654dbe4cb7fb938cc72aba475081eeb
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: CCAEC" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/5157