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

Details

Serval ID
serval:BIB_E6C7CFCAA97A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.
Journal
Cancer Research
Author(s)
Sivasankaran B., Degen M., Ghaffari A., Hegi M.E., Hamou M.F., Ionescu M.C., Zweifel C., Tolnay M., Wasner M., Mergenthaler S., Miserez A.R., Kiss R., Lino M.M., Merlo A., Chiquet-Ehrismann R., Boulay J.L.
ISSN
1538-7445
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
69
Number
2
Pages
458-465
Language
english
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.
Keywords
Amino Acid Sequence, Base Sequence, Brain Neoplasms, Cell Movement, Glioblastoma, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunohistochemistry, Molecular Sequence Data, Oligodendroglioma, Promoter Regions, Genetic, Receptor, Notch2, Response Elements, Signal Transduction, Tenascin, Transcriptional Activation
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2009 18:52
Last modification date
20/08/2019 16:09
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