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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2004-4-14
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pubmed:abstractText |
Human endostatin has an internal Asn-Gly-Arg (NGR) motif at position 126-128 following a proline at position 125. Asn-Gly-Arg-containing peptides have been shown to target tumour vasculature and inhibit aminopeptidase N activity. We previously compared the in vitro and in vivo biological activities of native endostatin and endostatin with a proline to alanine mutation (P125A-endostatin). P125A-endostatin exhibited greater inhibition of both endothelial cell proliferation and human ovarian cancer growth compared to native endostatin. Here we explore further the effects on biological activity of the P125A mutation, and show that aminopeptidase N is not involved. To determine whether the increased biological activity of the mutant was due to unmasking of downstream NGR-sequence, effect of endostatin on aminopeptidase N activity was investigated. Neither the native nor the P125A-endostatin inhibited aminopeptidase N. However, synthetic peptides consisting of the S118-T131 region of endostatin inhibited aminopeptidase N. These results suggest that the internal NGR site in native or mutant endostatin is not accessible to aminopeptidase N, and that this activity is not involved in the enhanced biological activity of the P125A form. P125A-endostatin bound to endothelial cells more efficiently than native endostatin and exhibited greater inhibition of not only proliferation but also migration of endothelial cells. P125A-endostatin also localised into tumour tissue to a higher degree than the native protein, and displayed greater inhibition of growth of colon cancer in athymic mice. Both proteins inhibited tumour cell-induced angiogenesis effectively. Real-time PCR analysis showed that both native and P125A-endostatin decreased expression of key proangiogenic growth factors. Vascular endothelial growth factor and angiopoietin 1 were downregulated more by the mutant. These studies suggest that the region around P125 can be modified to improve the biological activity of endostatin.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10049780,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10449407,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10562536,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10625665,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10626789,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10626820,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10676659,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10786683,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10792968,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10828022,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10837460,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-10910082,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11034081,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11103779,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11292666,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11336704,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11581192,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11606410,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-11959001,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-12147676,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-12209972,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-12354694,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-12359771,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-3802100,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-8640821,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-9008168,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-9389480,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-9430587,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15083196-9892206
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0007-0920
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
90
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1627-35
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:15083196-Amino Acid Substitution,
pubmed-meshheading:15083196-Angiopoietin-1,
pubmed-meshheading:15083196-Animals,
pubmed-meshheading:15083196-Cell Division,
pubmed-meshheading:15083196-Cell Movement,
pubmed-meshheading:15083196-Colonic Neoplasms,
pubmed-meshheading:15083196-Down-Regulation,
pubmed-meshheading:15083196-Endostatins,
pubmed-meshheading:15083196-Female,
pubmed-meshheading:15083196-Humans,
pubmed-meshheading:15083196-Mice,
pubmed-meshheading:15083196-Mice, Nude,
pubmed-meshheading:15083196-Neovascularization, Pathologic,
pubmed-meshheading:15083196-Ovarian Neoplasms,
pubmed-meshheading:15083196-Point Mutation,
pubmed-meshheading:15083196-Polymerase Chain Reaction,
pubmed-meshheading:15083196-Vascular Endothelial Growth Factor A
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pubmed:year |
2004
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pubmed:articleTitle |
Improved biological activity of a mutant endostatin containing a single amino-acid substitution.
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pubmed:affiliation |
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street, S E, Minneapolis, MN 55454, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
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