title: Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.
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.
authors.affiliation: Department of Research, Laboratory of Molecular Neuro-Oncology, University Hospital, Basel, Switzerland.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Sivasankaran
authors.forename: Martin
authors.initials: M
authors.lastname: Degen
authors.forename: Anthony
authors.initials: A
authors.lastname: Ghaffari
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hamou
authors.forename: Mihai-Constantin S
authors.initials: MC
authors.lastname: Ionescu
authors.forename: Christian
authors.initials: C
authors.lastname: Zweifel
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: Morten
authors.initials: M
authors.lastname: Wasner
authors.forename: Susanne
authors.initials: S
authors.lastname: Mergenthaler
authors.forename: André R
authors.initials: AR
authors.lastname: Miserez
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Maddalena M
authors.initials: MM
authors.lastname: Lino
authors.forename: Adrian
authors.initials: A
authors.lastname: Merlo
authors.forename: Ruth
authors.initials: R
authors.lastname: Chiquet-Ehrismann
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Boulay
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051883:Receptor, Notch2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D019063:Tenascin / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497764:NOTCH2 protein, human; C497570:RBPJ protein, human; D051883:Receptor, Notch2; D019063:Tenascin