Abstract
The fibulins are a family of secreted glycoproteins that are characterized by repeated epidermal-growth-factor-like domains and a unique C-terminus structure. Fibulins modulate cell morphology, growth, adhesion, and motility. Our initial basement membrane degradome screen using Cathepsin D, a tumor microenvironment-associated protease, contained fragments of fibulin-1 and full length fibulin-5. In this report, we evaluate the antiangiogenic activity of fibulin-1 and fibulin-5. Tumor studies demonstrate that both fibulin-1 and fibulin-5 suppress HT1080 tumor growth. CD31 labeling and TUNEL assay further reveal that fibulin-1 suppression of HT1080 tumor growth is associated with diminished angiogenesis and also enhanced apoptosis of endothelial cells and tumor cells. In contrast, fibulin-5 inhibits tumor angiogenesis with a minimal anti-apoptotic affect. Cathepsin D digestion of fibulin-1 produces a fragment with nearly the same molecular weight as fibulin-5, and this fragment (named Neostatin) inhibits endothelial cell proliferation. Additionally, degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Angiogenesis Inhibitors / genetics
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Angiogenesis Inhibitors / isolation & purification
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Angiogenesis Inhibitors / metabolism
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Basement Membrane / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / isolation & purification
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Calcium-Binding Proteins / metabolism
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Calcium-Binding Proteins / pharmacology*
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Cathepsin D / metabolism
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Cattle
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Cell Proliferation / drug effects
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Cloning, Molecular
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Conserved Sequence
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / isolation & purification
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Extracellular Matrix Proteins / metabolism
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Extracellular Matrix Proteins / pharmacology*
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Humans
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Molecular Sequence Data
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Molecular Weight
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Neoplasms / pathology*
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Recombinant Proteins / genetics
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Sequence Alignment
Substances
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Angiogenesis Inhibitors
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Calcium-Binding Proteins
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Extracellular Matrix Proteins
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FBLN5 protein, human
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Recombinant Proteins
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fibulin
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Cathepsin D