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PEDS Advance Access published online on June 24, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzi040
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received December 7, 2004
Revised April 21, 2005
Accepted May 18, 2005

Article

Anti-angiogenic effect of an insertional fusion protein of human basic fibroblast growth factor and ribonuclease-1

Tetsu Hayashida 1, Masakazu Ueda 1*, Koichi Aiura 1, Hiroko Tada 2, Masayuki Onizuka 2, Masaharu Seno 2, Hidenori Yamada 2, and Masaki Kitajima 1

1 Department of Surgery, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan
2 Department of Bioscience and Biotechnology, Faculty of Engineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan

* To whom correspondence should be addressed.
Masakazu Ueda, E-mail: m_ueda{at}sc.itc.keio.ac.jp


  Abstract

Human pancreatic ribonuclease-1 (RNase1) does not exhibit its cytotoxicity unless it is artificially internalized into the cytosol. Furthermore, once it encounters the cytosolic RNase inhibitor (RI), the activity of RNase1 is seriously reduced. To achieve the cellular targeting of RNase1 and the blocking of RI binding simultaneously, the basic fibroblast growth factor (bFGF) sequence was inserted into RNase1 at the RI binding site using a gene fusion technique. The effect of this fusion protein, CL-RFN89, on the angiogenesis, which was accelerated by FGF-FGF receptor interaction, was investigated. It was shown by using fluorescein-labeled CL-RFN89, that the binding to human umbilical vein endothelial cells (HUVECs) was dependent on the existence of the FGF receptors. In addition, CL-RFN89 inhibited the cellular growth of HUVECs in vitro and also inhibited the tube formation, using a three-dimensional tube formation assay. Furthermore, this fusion protein was shown to prevent in vivo tumor cell-induced angiogenesis, using the mouse dorsal air sac assay. These results demonstrated that CL-RFN89 inhibits angiogenesis in vitro and in vivo and that it can be expected to be a potent antiangiogenic agent.

Keywords: angiogenesis; basic fibroblast growth factor; fusion protein; molecular targeting; ribonuclease.
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