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Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas

Sivasankaran, B. and Degen, M. and Ghaffari, A. and Hegi, M. E. and Hamou, M. F. and Ionescu, M. C. and Zweifel, C. and Tolnay, M. and Wasner, M. and Mergenthaler, S. and Miserez, A. R. and Kiss, R. and Lino, M. M. and Merlo, A. and Chiquet-Ehrismann, R. and Boulay, J. L.. (2009) Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas. Cancer research : a journal of the American Association for Cancer Research, Vol. 69. pp. 458-465.

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Official URL: http://edoc.unibas.ch/dok/A6007172

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Abstract

Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Allgemeine Pathologie (Tolnay)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Allgemeine Pathologie (Tolnay)
UniBasel Contributors:Miserez, Andre Roger and Tolnay, Markus
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for Cancer Research
ISSN:0008-5472
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:22
Deposited On:24 May 2013 09:05

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