Accessible Requires Authentication Published by De Gruyter November 13, 2012

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

Susan Notohamiprodjo, Roghieh Djafarzadeh, Nicole Rieth, Monika Hofstetter, Carsten Jaeckel and Peter J. Nelson
From the journal Biological Chemistry

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.


Corresponding author: Peter J. Nelson, Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Universität München, Arbeitsgruppe Klinische Biochemie, Schillerstrasse 42, D-80336, Münich, Deutschland

Received: 2012-5-2
Accepted: 2012-8-20
Published Online: 2012-11-13
Published in Print: 2012-12-01

©2012 by Walter de Gruyter Berlin Boston