Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-β1 activation and reduces regulatory ID gene expression

Notohamiprodjo, Susan; Djafarzadeh, Roghieh; Rieth, Nicole; Hofstetter, Monika; Jaeckel, Carsten und Nelson, Peter J. (2012): Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-β1 activation and reduces regulatory ID gene expression. In: Biological Chemistry, Vol. 393, No. 12: pp. 1463-1470

Abstract

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1 stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1–GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1–GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF-β1/SMAD and BMP pathways resulted from TIMP-1–GPI treatment. These events were linked to reduced TGF-β1 signaling mediated by inhibition of proteolytic processing of latent TGF-β1 by TIMP-1–GPI.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1431-6730
• Alliance/National Licence: This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
• Language: English