Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-24077
Tritschler, I; Gramatzki, D; Capper, D; Mittelbronn, M; Meyermann, R; Saharinen, J; Wick, W; Keski-Oja, J; Weller, M (2009). Modulation of TGF-beta activity by latent TGF-beta-binding protein 1 in human malignant glioma cells. International Journal of Cancer, 125(3):530-540.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology|
|DDC:||610 Medicine & health|
|Deposited On:||18 Nov 2009 14:38|
|Last Modified:||27 Nov 2013 22:19|
|Additional Information:||The definitive version is available at www.blackwell-synergy.com|
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