Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.
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Sivasankaran, Balasubramanian, Degen, Martin, Ghaffari, Anthony, Hegi, Monika E, Hamou, Marie-France, Ionescu, Mihai-Constantin S, Zweifel, Christian, Tolnay, Markus, Wasner, Morten, Mergenthaler, Susanne, Miserez, Andre R, Kiss, Robert, Lino, Maddalena M, Merlo, Adrian, Chiquet, Ruth and Boulay, Jean-Louis (2009) Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas. Cancer Research, 69 (2). pp. 458-465. ISSN 1538-7445
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.
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution |
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| Date Deposited: | 14 Dec 2009 13:50 |
| Last Modified: | 31 Jan 2013 01:01 |
| URI: | https://oak.novartis.com/id/eprint/980 |