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Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I
Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein in cartilage matrix that inhibits angiogenesis. It contains two distinctive structural domains: the N-terminal third of the molecule is a hydrophilic domain that contains O-linked and N-linked oligosaccharide chains, and the C-terminal two-thirds is...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492907/ https://www.ncbi.nlm.nih.gov/pubmed/22429838 http://dx.doi.org/10.1111/j.1349-7006.2012.02276.x |
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author | Miura, Shigenori Kondo, Jun Kawakami, Toru Shukunami, Chisa Aimoto, Saburo Tanaka, Hideyuki Hiraki, Yuji |
author_facet | Miura, Shigenori Kondo, Jun Kawakami, Toru Shukunami, Chisa Aimoto, Saburo Tanaka, Hideyuki Hiraki, Yuji |
author_sort | Miura, Shigenori |
collection | PubMed |
description | Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein in cartilage matrix that inhibits angiogenesis. It contains two distinctive structural domains: the N-terminal third of the molecule is a hydrophilic domain that contains O-linked and N-linked oligosaccharide chains, and the C-terminal two-thirds is a hydrophobic domain that contains all of the cysteine residues. In the present study, we have attempted to further uncover the structural requirements for ChM-I to exert anti-angiogenic activity by monitoring its inhibition of the vascular endothelial growth factor (VEGF)-A-induced migration of HUVEC in vitro. Site-directed mutagenesis experiments revealed that the cyclic structure formed by the disulfide bridge between Cys(83) and Cys(99) in human ChM-I is indispensable for its anti-angiogenic function. Moreover, the C-terminal hydrophobic tail (from Trp(111) to Val(120)) was found to play an important role in ensuring the effectiveness of ChM-I activity on HUVEC. A synthetic cyclic peptide corresponding to the ChM-I region between Ile(82) to Arg(100) also inhibited the migration of HUVEC, while replacing the Cys(83) and Cys(99) residues in this peptide with Ser completely negated this inhibitory activity. An additional synthetic cyclic peptide harboring the hydrophobic C-terminal tail of ChM-I clearly mimicked the inhibitory action of this protein on the migration of HUVEC and successfully inhibited tumor angiogenesis and growth in a xenograft mouse model of human chondrosarcoma. |
format | Online Article Text |
id | pubmed-3492907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-34929072012-11-09 Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I Miura, Shigenori Kondo, Jun Kawakami, Toru Shukunami, Chisa Aimoto, Saburo Tanaka, Hideyuki Hiraki, Yuji Cancer Sci Original Articles Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein in cartilage matrix that inhibits angiogenesis. It contains two distinctive structural domains: the N-terminal third of the molecule is a hydrophilic domain that contains O-linked and N-linked oligosaccharide chains, and the C-terminal two-thirds is a hydrophobic domain that contains all of the cysteine residues. In the present study, we have attempted to further uncover the structural requirements for ChM-I to exert anti-angiogenic activity by monitoring its inhibition of the vascular endothelial growth factor (VEGF)-A-induced migration of HUVEC in vitro. Site-directed mutagenesis experiments revealed that the cyclic structure formed by the disulfide bridge between Cys(83) and Cys(99) in human ChM-I is indispensable for its anti-angiogenic function. Moreover, the C-terminal hydrophobic tail (from Trp(111) to Val(120)) was found to play an important role in ensuring the effectiveness of ChM-I activity on HUVEC. A synthetic cyclic peptide corresponding to the ChM-I region between Ile(82) to Arg(100) also inhibited the migration of HUVEC, while replacing the Cys(83) and Cys(99) residues in this peptide with Ser completely negated this inhibitory activity. An additional synthetic cyclic peptide harboring the hydrophobic C-terminal tail of ChM-I clearly mimicked the inhibitory action of this protein on the migration of HUVEC and successfully inhibited tumor angiogenesis and growth in a xenograft mouse model of human chondrosarcoma. Blackwell Publishing Ltd 2012-07 2012-04-27 /pmc/articles/PMC3492907/ /pubmed/22429838 http://dx.doi.org/10.1111/j.1349-7006.2012.02276.x Text en © 2012 Japanese Cancer Association http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Articles Miura, Shigenori Kondo, Jun Kawakami, Toru Shukunami, Chisa Aimoto, Saburo Tanaka, Hideyuki Hiraki, Yuji Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title | Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title_full | Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title_fullStr | Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title_full_unstemmed | Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title_short | Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I |
title_sort | synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-i |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492907/ https://www.ncbi.nlm.nih.gov/pubmed/22429838 http://dx.doi.org/10.1111/j.1349-7006.2012.02276.x |
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