53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma Journal Article
| Authors: | Squatrito, M.; Vanoli, F.; Schultz, N.; Jasin, M.; Holland, E. C. |
| Article Title: | 53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma |
| Abstract: | 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 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 53BP1 null 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. ©2012 AACR. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; nonhuman; glioma; brain neoplasms; animal cell; mouse; animals; mice; animal tissue; dna damage; cell survival; cell cycle; apoptosis; animal experiment; animal model; in vivo study; cancer cell culture; in vitro study; heterozygote; radiation response; dna; heterozygosity; intracellular signaling peptides and proteins; glioblastoma; ionizing radiation; cell cycle arrest; radiosensitivity; binding protein; gene silencing; disease models, animal; tumor suppressor protein; cell protection; gene knockdown techniques; dna damage checkpoint; haploinsufficiency; cancer prognosis; dna end-joining repair; dna end joining repair; p53 binding protein 1 |
| Journal Title: | Cancer Research |
| Volume: | 72 |
| Issue: | 20 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-10-15 |
| Start Page: | 5250 |
| End Page: | 5260 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-12-0045 |
| PROVIDER: | scopus |
| PUBMED: | 22915756 |
| PMCID: | PMC3771704 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: CNREA" - "Source: Scopus" |
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