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RAD51 can inhibit PDGFB-induced gliomagenesis and genomic instability
Karolinska Institutet, Institutionen för onkologi-patologi. (Monica Nistér)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2011 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 13, no 12, 1277-1287 p.Article in journal (Refereed) Published
Abstract [en]

Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.

Place, publisher, year, edition, pages
2011. Vol. 13, no 12, 1277-1287 p.
Keyword [en]
genomic instability, glioma, PDGF-B, RAD51, replicative stress
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-109482DOI: 10.1093/neuonc/nor131ISI: 000297936300004OAI: oai:DiVA.org:uu-109482DiVA: diva2:272597
Available from: 2009-10-15 Created: 2009-10-15 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Cellular Origin and Development of Glioma
Open this publication in new window or tab >>Cellular Origin and Development of Glioma
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gliomas are the most common primary tumors of the central nervous system believed to arise from glial cells. Invasive growth and inherent propensity for malignant progression make gliomas incurable despite extensive treatment. I have developed a life-like orthotopic glioma model and used this and other in vivo models to study basic mechanisms of glioma development and treatment.

Previous studies had indicated that experimental gliomas could arise from glial stem cells and astrocytes. The present thesis describes the making and characterization of a novel mouse model, Ctv-a, where gliomas are induced from oligodendrocyte progenitor cells (OPCs). Our study shows that OPCs have the capacity to give rise to gliomas and suggests in light of previous data that the differentiation state of the cell of origin affects tumor malignancy.

CDKN2A encodes p16INK4a and p14ARF (p19Arf in mouse) commonly inactivated in malignant glioma. Their roles in experimental glioma have been extensively studied and both proteins have tumor suppressor functions in glial stem cells and astrocytes. Here, we demonstrate that p19Arf only could suppress gliomagenesis in OPCs while p16Ink4a had no tumor suppressive effect.

Functional DNA repair is pivotal for maintaining genome integrity, eliminating unsalvageable cells and inhibiting tumorigenesis. We have studied how RAD51, a central protein of homology-directed repair, affected experimental glioma development and have found that expression of RAD51 may protect against genomic instability and tumor development.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a central feature of malignant progression in glioma. Antiangiogenic treatment by inhibition of vascular endothelial growth factor receptor signaling is used in the clinic for treatment of some cancers. We have investigated the effect of an alternative antiangiogenic protein, histidine-rich glycoprotein (HRG), on glioma development and found that HRG could inhibit the formation of malignant gliomas and completely prevent the formation of glioblastoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 491
Keyword
Glioma, brain tumor, PDGF, RCAS/TV-A, cell of origin, glial cell, oligodendrocyte progenitor cell, DNA repair, homology-directed repair, RAD51, angiogenesis, histidine-rich glycoprotein
National Category
Cell and Molecular Biology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-109486 (URN)978-91-554-7640-3 (ISBN)
Public defence
2009-12-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-13 Created: 2009-10-15 Last updated: 2009-11-13Bibliographically approved

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