Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas Journal Article
| Authors: | See, W. L.; Miller, J. P.; Squatrito, M.; Holland, E.; Resh, M. D.; Koff, A. |
| Article Title: | Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas |
| Abstract: | The tumor suppressive activities of the Kip-family of cyclin-dependent kinase (cdk) inhibitors often go beyond their role directly regulating the cell cycle. In this study, we show that p27 enhances Rad51 accumulation during repair of double-strand DNA breaks. Progression of platelet-derived growth factor (PDGF)-induced oligodendrogliomas was accelerated in mice lacking the cyclin-cdk binding activities of p27 kip1. To understand how p27 deficiency contributes, cell lines were developed from RCAS-PDGF infection of nestin-tv-a brain progenitor cells in culture. p27 deficiency did not affect cell proliferation in early passage cell lines; however, the absence of p27 affected chromosomal stability. In p27-deficient cells, the activation of Atm and Chk2 and the accumulation of γ-H2AX was unaffected when compared with wild-type cells, and the number of phospho-histone H3 staining mitotic cells was decreased, consistent with G2/M checkpoint activation. However, the percentage of Rad51 foci-positive cells was decreased, and the kinase activity that targets the C-terminus of BRCA2, regulating BRCA2/Rad51 interactions, was increased in lysates derived from p27-deficient cells. Increased numbers of chromatid breaks in p27-deficient cells that adapted to the checkpoint were also observed. These findings suggest that Rad51-dependent repair of double-stranded breaks was hindered in p27-deficient cells, leading to chromosomal instability, a hallmark of cancers with poor prognosis. © 2010 Macmillan Publishers Limited All rights reserved. |
| Keywords: | platelet derived growth factor; s6 kinase; controlled study; survival rate; nonhuman; glioma; brain neoplasms; cell proliferation; mitosis; animal cell; mouse; animals; mice; mice, knockout; actin; mre11 protein; animal tissue; dna damage; mus; cell division; dna repair; carboxy terminal sequence; protein protein interaction; glial fibrillary acidic protein; neural stem cell; cancer cell culture; enzyme activity; brca2 protein; wild type; carcinogenesis; chromatid; cyclin dependent kinase inhibitor 1b; histone h3; protein p27; cyclin-dependent kinase inhibitor p27; platelet-derived growth factor; staining; atm protein; mitogen activated protein kinase 1; mitogen activated protein kinase 3; dna breaks, double-stranded; chromosomal instability; double stranded dna break; oligodendroglioma; checkpoint kinase 2; cell cycle g2 phase; cell cycle m phase; genes, reporter; tumor suppressor; ku antigen; cyclin d1; cyclin a; protein p21; nestin; neuron specific nuclear protein; phosphotransferase; histone h2ax; transcription factor sox2; rad51 protein; cell lysate; g2 phase; platelet derived growth factor beta receptor; mouse model; growth substances; p27 |
| Journal Title: | Oncogene |
| Volume: | 29 |
| Issue: | 12 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-03-25 |
| Start Page: | 1720 |
| End Page: | 1731 |
| Language: | English |
| DOI: | 10.1038/onc.2009.465 |
| PUBMED: | 20062078 |
| PROVIDER: | scopus |
| PMCID: | PMC2845739 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: ONCNE" - "Source: Scopus" |
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