Inhibition of cell growth by a fused protein of human ribonuclease 1 and human basic fibroblast growth factor.
Pancreatic-type RNases are considered to have cytotoxic potential due to their ability to degrade RNA molecules when they enter the cytosol. However, most of these RNases show little cytotoxicity because cells have no active uptake mechanism for these RNases and because the ubiquitous cytoplasmic RNase inhibitor is considered to play a protective role against the endocytotic leak of RNases from the outside of cells. To study the cytotoxic potential of RNase toward malignant cells targeting growth factor receptors, the C-terminus of human RNase 1 was fused to the N-terminus of human basic fibroblast growth factor (bFGF). This RNase-FGF fused protein effectively inhibited the growth of mouse melanoma cell line B16/BL6 with high levels of cell surface FGF receptor. This effect appeared to result from prolongation of the overall cell cycle rather than the killing of cells or specific arrest in a particular phase of the cell cycle. Thus, human RNase 1 fused to a ligand of cell surface molecules, such as the FGF receptor, is shown to be an effective candidate for a selective cell targeting agent with low toxic effects on normal cell types.
Futami
J
J
Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530 and Department of Surgery, Keio University School of Medicine,Tokyo 160-8582, Japan.
Seno
M
M
Ueda
M
M
Tada
H
H
Yamada
H
H
D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D008545:Melanoma; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012259:Ribonuclease, Pancreatic / Q000235:genetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D010446:Peptide Fragments; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D019000:Phosphotyrosine; D012259:Ribonuclease, Pancreatic