title: Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF- β 1 activation and reduces regulatory ID gene expression.
abstract: Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1stoichiometric 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- β 1/SMAD and BMP pathways resulted from TIMP-1 - GPI treatment. These events were linked to reduced TGF- β 1 signaling mediated by inhibition of proteolytic processing of latent TGF- β 1 by TIMP-1 - GPI.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Universit at Mu nchen, Arbeitsgruppe Klinische Biochemie, Schillerstrasse 42, D-80336, Munich , Deutschland.
authors.forename: Susan
authors.initials: S
authors.lastname: Notohamiprodjo
authors.forename: Roghieh
authors.initials: R
authors.lastname: Djafarzadeh
authors.forename: Nicole
authors.initials: N
authors.lastname: Rieth
authors.forename: Monika
authors.initials: M
authors.lastname: Hofstetter
authors.forename: Carsten
authors.initials: C
authors.lastname: Jaeckel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
mesh_terms: D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D017261:Glycosylphosphatidylinositols; D011993:Recombinant Fusion Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D020782:Matrix Metalloproteinases