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Differential roles of p16Ink4a and p19Arf in suppressing gliomagenesis from oligodendrocyte progenitor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology. (Lene Uhrbom)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Lene Uhrbom)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Lene Uhrbom)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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CDKN2a encodes the tumor suppressor proteins p16INK4a and p14ARF (p19Arf in mouse) whose functions are frequently lost in human glioblastoma. From previous studies using the RCAS/TV-Atv-a mouse model we have shown that p16Ink4a and p19Arf individually and combined couldan suppress glioma development in Nestin expressing cells (in Ntv-a mice) and in Gfap expressing cells (in Gtv-a mice) (Uhrbom, Dai et al. 2002; Uhrbom, Kastemar et al. 2005; Tchougounova, Kastemar et al. 2007). Recently, we showed that oligodendrocyte progenitor cells (OPCs) could act as cell of origin for glioma by making a Ctv-a mouse in which CNPase expressing cells couldan be targeted by retroviral infection (Lindberg, Kastemar et al. 2009). Here In the current study we have investigated the roles of p16Ink4a and p19Arf in tumor development from OPCs.

Unexpectedly, we found that p19Arf only only could suppress oncogene induced gliomagenesis. Loss of Arf caused significantly increased incidence and malignancy of PDGF-B induced tumors and decreased survival compared to Ctv-a wt mice. In addition, Arf deficiency facilitated K-RAS+AKT induced glioma development. Loss of Ink4a, however, lead to nocould not enable tumor induction by (K-RAS++AKT and caused a slight decrease in (PDGF-B) induced tumor incidence. Similarly, wWhen inducing tumors in adult Ctv-a mice we found that Arf loss but not Ink4a loss  enabled tumor induction. Taken together, our data suggest that p19Arf but not p16Ink4a is a tumor suppressor in OPCs of both newborn and adult mice.

National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-109387OAI: oai:DiVA.org:uu-109387DiVA: diva2:272192
Available from: 2009-10-14 Created: 2009-10-14 Last updated: 2010-01-14
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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