Molecular and Cellular Pathobiology 53BP1 Is a Haploinsufficient Tumor Suppressor and Protects Cells from Radiation Response in Glioma
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چکیده
The DNA damage response (DDR) plays a crucial role in tumor development in different tissues. Here, we show that p53-binding protein 1 (53BP1), a key element of the DDR, is heterozygously lost in approximately 20% of human glioblastomamultiforme (GBM) specimens, primarily of the Proneural subtype, and low 53BP1 expression levels are associated with worse prognosis. We present evidence that 53BP1 behaves as haploinsufficient tumor suppressor in a mouse model of platelet-derived growth factor–induced gliomagenesis. We also show that very low level of 53BP1 as found in 53BP1null gliomas or robust 53BP1 gene silencing in glioma cell lines (but not 53BP1 heterozygous tumors or partial gene knockdown) sensitizes glioma cells to ionizing radiation (IR), both in vitro and in vivo.We further show the 53BP1 gene silencing induces defects in the nonhomologous end-joining (NHEJ) DNA repair pathway. These deficiencies lead to a failure to fully repair the damaged DNA upon exposure of glioma cells to IR with a consequent prolonged cell-cycle arrest and increased apoptosis. Our data suggest that either 53BP1 or other NHEJ components may be critical molecules to be pharmacologically targeted in GBM in combination with standard therapies. Cancer Res; 72(20); 5250–60. 2012 AACR. Introduction The p53-binding protein 1 (53BP1) was initially identified as a protein that interacts with the DNA-binding domain of wildtype but not mutant p53, having the ability to modulate p53mediated transcription activation (1, 2). 53BP1 has subsequently been shown to also have p53-independent functions as a key mediator of the DNA-damage response (DDR) and a direct modulator of DNA double-strand break (DSB) repair (3). 53BP1-deficient cells exhibit increased genomic instability and consequently 53BP1 null mice are highly radiation sensitive, display growth retardation and are tumor prone (4, 5). Even though a critical role of the DDR pathway in tumor formation and modulation of therapeutic response has been established recently, it is unclear whether 53BP1 takes an active part in these processes, and if so in which tumor type. Here, we show that 53BP1 is frequently heterozygously lost in glioblastoma multiforme (GBM) and behaves as a haploinsufficient tumor suppressor in a mouse model of glioma. Gliomas are the most frequent primary malignancies in the central nervous system (CNS), with GBM being the most malignant form of gliomas.We have previously shown that some essential components of the DDR, such as ATM, Chk2, and p53, are frequently inactivated in GBM and exert a crucial activity during in glioma development and radiation response (6). Contrasting with its role as a tumor suppressor when partly lost, complete loss of 53BP1 in glioma cells increases radiosensitivity both in vitro and in vivo. We present evidence that the radiation sensitivity might be related to 53BP1 role in modulating nonhomologous end-joining (NHEJ) DNA repair. Material and Methods TCGA analysis The analysis of the The Cancer Genome Atlas (TCGA) dataset for GBM was conducted through the cBio Cancer Genomics Portal (7), based on the January 24, 2012 Broad Firehose run of TCGA data. Copy number alterations (CNA), expression and survival data of patients are also presented in Supplementary Tables S1 and S2. Mice and generation of murine gliomas 53bp1 / mice (4) were obtained from Titia de Lange. Athymic Nude-Foxn1 mice were purchased from Harlan Laboratories. Nestin-tv-a (Ntv-a) mice, and procedures for RCAS-mediated gliomagenesis have been described previously (8). All animal experiments were done in accordance with protocols approved by the Institutional Animal Care and Use Committee of Memorial Sloan-Kettering Cancer Center and followed NIH guidelines for animal welfare. Histology, immunohistochemistry, and TUNEL assay Tissues were fixed in 10% neutral-buffered formalin and subsequently embedded in paraffin, following standard procedures. Immunohistochemical and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) Authors' Affiliations: Departments of Cancer Biology and Genetics, Developmental Biology, Computational Biology, Surgery (Neurosurgery), and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). CorrespondingAuthors:MassimoSquatrito, 408 E69th Street, NewYork, NY 10021. Phone: 646-888-2056; Fax: 646-422-0231. E-mail: [email protected]; and Eric C. Holland, E-mail: [email protected] doi: 10.1158/0008-5472.CAN-12-0045 2012 American Association for Cancer Research. Cancer Research Cancer Res; 72(20) October 15, 2012 5250 on April 20, 2017. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst August 21, 2012; DOI: 10.1158/0008-5472.CAN-12-0045
منابع مشابه
53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma.
The DNA damage response (DDR) plays a crucial role in tumor development in different tissues. Here, we show that p53-binding protein 1 (53BP1), a key element of the DDR, is heterozygously lost in approximately 20% of human glioblastoma multiforme (GBM) specimens, primarily of the Proneural subtype, and low 53BP1 expression levels are associated with worse prognosis. We present evidence that 53B...
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تاریخ انتشار 2012