Engineering of human coagulation factor X variants activated by prostate-specific antigen |
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Authors: | Tina Völkel Hans-Heinrich Heidtmann Rolf Müller Roland E Kontermann |
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Institution: | 1. Institut für Molekularbiologie und Tumorforschung, Philipps-Universit?t, Emil-Mannkopff-Str.2, 35033, Marburg, Germany 2. Zentrum für Innere Medizin, Abt. H?matologie und Onkologie, Philipps-Universit?t, Baldingerstrasse, 35033, Marburg, Germany 4. Institut für Zellbiologie und Immunologie, Universit?t Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
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Abstract: | In this study, we present a novel approach for the induction of tumor vessel thrombosis using genetically modified coagulation
factor X. Human factor X was engineered in its activation peptide in a way that it can be specifically activated by prostate-specific
antigen (PSA), a tumor-specific proteinase secreted into the bloodstream by prostate cancer cells. For this purpose we inserted
different sequences of known PSA cleavage sites from the natural substrate of PSA, semenogelin I, into the activation peptide
of factor X. One FX variant (FX-V4) was further optimized by site-directed mutagenesis of the P2 position and the P5 position
(FX-V4-P2YP5R). After preincubation with PSA, FX-V4-P2YP5R was able to efficiently induce coagulation in vitro. These FX variants
should be useful for site-specific induction of blood coagulation in the tumor vasculature. |
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Keywords: | Prostate-specific antigen site-directed mutagenesis coagulation factor tumor proteinase activation peptide |
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