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Modulation of TGF-beta activity by latent TGF-beta-binding protein 1 in human malignant glioma cells.

Abstract
High biological activity of the transforming growth factor (TGF)-beta-Smad pathway characterizes the malignant phenotype of malignant gliomas and confers poor prognosis to glioma patients. Accordingly, TGF-beta has become a novel target for the experimental treatment of these tumors. TGF-beta is processed by furin-like proteases (FLP) and secreted from cells in a latent complex with its processed propeptide, the latency-associated peptide (LAP). Latent TGF-beta-binding protein 1 (LTBP-1) covalently binds to this small latent TGF-beta complex (SLC) and regulates its function, presumably via interaction with the extracellular matrix (ECM). We report here that the levels of LTBP-1 protein in vivo increase with the grade of malignancy in gliomas. LTBP-1 is associated with the ECM as well as secreted into the medium in cultured malignant glioma cells. The release of LTBP-1 into the medium is decreased by the inhibition of FLP activity. Gene-transfer mediated overexpression of LTBP-1 in glioma cell lines results in an increase inTGF-beta activity. Accordingly, Smad2 phosphorylation as an intracellular marker of TGF-beta activity is enhanced. Conversely, LTBP-1 gene silencing reduces TGF-beta activity and Smad2 phosphorylation without affecting TGF-beta protein levels. Collectively, we identify LTBP-1 as an important modulator of TGF-beta activation in glioma cells, which may contribute to the malignant phenotype of these tumors.
AuthorsIsabel Tritschler, Dorothee Gramatzki, David Capper, Michel Mittelbronn, Richard Meyermann, Juha Saharinen, Wolfgang Wick, Jorma Keski-Oja, Michael Weller
JournalInternational journal of cancer (Int J Cancer) Vol. 125 Issue 3 Pg. 530-40 (Aug 01 2009) ISSN: 1097-0215 [Electronic] United States
PMID19431147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • LTBP1 protein, human
  • Latent TGF-beta Binding Proteins
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
Topics
  • Astrocytoma (metabolism)
  • Brain Neoplasms (metabolism)
  • Cell Line, Tumor
  • Cell Proliferation
  • Extracellular Matrix (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma (metabolism)
  • Glioma (metabolism)
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Latent TGF-beta Binding Proteins (metabolism)
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Phosphorylation
  • Polymerase Chain Reaction
  • Signal Transduction
  • Smad2 Protein (metabolism)
  • Transforming Growth Factor beta (metabolism)
  • Up-Regulation

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