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กก Guo-fu
Hu Angiogenin is a potent tumor angiogenic protein whose concentration in serum is elevated in patients affected by various types of cancers. Inhibition of angiogenin is known to prevent human tumor growth in athymic mice. We have been studying the mechanism by which angiogenin induces neovascularization and have found that it interacts with endothelial and smooth muscle cells, stimulates a second messenger response, induces cell proliferation, and organizes cultured cells to form tubular structures. It also mediates cell adhesion, activates proteases and induces cell invasion. Currently, we are focusing on the following mechanistic studies: Nuclear
function of angiogenin
Exogenous angiogenin undergoes nuclear
translocation in endothelial and smooth muscle cells in a process that is rapid,
specific, dependent on the cell density but independent of microtubule network
and lysosomal processing. Inhibition of nuclear translocation by neomycin or
through mutagenesis abolishes angiogenic activity. Upon nuclear translocation
angiogenin is accumulated in the nucleolus, binds to the promoter region of
ribosomal RNA gene and stimulates rRNA transcription, a process essential for
protein translation and cell growth. The angiogenin-binding DNA sequences have
been identified, characterized and shown to have promoter activity in an
angiogenin-dependent manner. We are currently investigating the transcription
stimulatory activity of angiogenin in a broader aspect and by means of antisense
and targeted gene disruption technologies to characterize the involvement of
angiogenin in tumor growth and angiogenesis induced by other angiogenic stimuli. Anti-angiogenic
activity of neomycin and derivatives
Neomycin was identified as a potent anti-angiogenesis
agent through our ongoing effort to elucidate the mechanism by which angiogenin
is translocated to the cell nucleus. Neomycin inhibits nuclear translocation of
angiogenin, thereby abolishing both the mitogenic and angiogenic activity of
angiogenin. Recent results showed that while neomycin is a more potent and
specific inhibitor of angiogenin than of other angiogenic factors, it acts as a
general inhibitor for the angiogenic proteins including aFGF, bFGF and EGF whose
capacity to induce angiogenesis is also related to nuclear translocation.
Studies are underway to assess the anti-tumor activity of neomycin and to
investigate its antiangiogenic mechanism for the purpose of developing less
toxic angiogenesis inhibitors based on the scaffold of neomycin. Angiogenin
receptors and binding proteins
Angiogenin binds to various molecules that are
expressed on the cell surface under different conditions. When the cells are
confluent, angiogenin binds to the a-smooth
muscle types of actin and induces cell invasion and migration via activation of
tPA and plasmin. When cells are under sparse culture, angiogenin binds to a 170
kDa putative receptor to induce phosphorylation of MAP kinases and cell
proliferation. Structural characterization of this putative receptor as well as
other angiogenin binding molecules is underway. References
Hu
G-F, Xu C-J, and Riordan JF. Human Angiogenin Is Rapidly Translocated to the
Nucleus
of
Human Umbilical Vein Endothelial Cells and Binds to DNA. J.
Cell Biochem. 76: 452-462, 2000 Hu
G-F, Kim H-J, Xu C-J, and Riordan JF. Fibroblast Growth Factors are Translocated
to the Nucleus of Human Endothelial Cells in a Microtubule and Lysosome
Independent Pathway. Biochem. Biophys.
Res. Commun. 273: 551-556, 2000. Hu
G-F, Vallee BL. Angiogenin. In: Kress T, and Vale R, editors. Guidebook
to the Extracellular Matrix and Adhesion Proteins. Oxford University Press,
1999, p 33-36. Hu
G-F, Riordan JF, and Vallee BL.. Angiogenin. In: Aggarwal BB, editor. Human
Cytokines: Handbook for Basic and Clinical Research. Vol. 3, Blackwell
Science, Inc., 1998, p 67-91. Hu
G-F. Neomycin inhibits angiogenin-induced angiogenesis. Proc.
Natl. Acad. Sci. USA 95: 9791-9795, 1998. Hu
G-F. Copper Stimulates Proliferation of Human Endothelial Cells Under Culture. J.
Cell Biochem. 69: 326-335, 1998. Nobile
V, Russo N, Hu G-F, and Riordan JF. Inhibition of Human Angiogenin by DNA
Aptamers: Nuclear Co-localization of an Angiogenin-Inhibitor Complex. Biochemistry
37:6857-6863, 1998. Hu
G-F, Riordan JF, and Vallee BL. A putative angiogenin receptor in angiogenin-responsive
human endothelial cells. Proc. Natl. Acad.
Sci. USA 94: 2204-2209, 1997. Li
R, Riordan JF, and Hu G-F. Nuclear Translocation of Human Angiogenin in Cultured
Human Umbilical Artery Endothelial Cells Is Microtubule and Lysosome
Independent. Biochem. Biophys. Res. Commun.
238: 305-312, 1997. Hu
G-F. Limited proteolysis of angiogenin by elastase is accelerated by plasminogen.
J. Protein Chem. 16: 669-679, 1997. Hu
G-F, Riordan JF, and Vallee BL. Angiogenin promotes invasiveness of cultured
endothelial cells by stimulation of cell-associated proteolytic activities. Proc.
Natl. Acad. Sci. USA 91: 12096-12100, 1994. Hu
G-F, Strydom DJ, Fett, Riordan JF, and Vallee BL. Actin is a binding protein for
angiogenin. Proc. Natl. Acad. Sci. USA
90: 1217-1221, 1993. Hu
G-F, and Riordan JF. Angiogenin enhances actin acceleration of plasminogen
activation. Biochem. Biophys. Res. Commun.
197: 682-687, 1993. Hu G-F, Chang S-I, Riordan JF, and Vallee BL. An angiogenin-binding protein from endothelial cells. Proc. Natl. Acad. Sci. USA 88: 2227-2231, 1991. |