Modulation of TGF-β activity by latent TGF-β-binding protein 1 in human malignant glioma cells
| Autor: | Wolfgang Wick, Jorma Keski-Oja, Michel Mittelbronn, Isabel Tritschler, Juha Saharinen, David Capper, Richard Meyermann, Michael Weller, Dorothee Gramatzki |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Immunoblotting Smad2 Protein Astrocytoma Biology Polymerase Chain Reaction Extracellular matrix 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta Cell Line Tumor Glioma medicine Humans Phosphorylation Cell Proliferation Oligonucleotide Array Sequence Analysis 030304 developmental biology 0303 health sciences R-SMAD Brain Neoplasms Binding protein Biological activity TGF beta receptor 2 Endoglin medicine.disease Immunohistochemistry Extracellular Matrix Up-Regulation 3. Good health Gene Expression Regulation Neoplastic Phenotype Latent TGF-beta Binding Proteins Oncology 030220 oncology & carcinogenesis Cancer research Signal transduction Glioblastoma Signal Transduction |
| Zdroj: | International Journal of Cancer. 125:530-540 |
| ISSN: | 1097-0215 0020-7136 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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