| Genetic construction and properties of a diphtheria toxin-related substance P fusion protein: in vitro destruction of cells bearing substance P receptors. | |
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MedLine Citation:
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PMID: 8692995 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have genetically replaced the native receptor binding domain of diphtheria toxin with an extended form of substance P (SP): SP-glycine (SP-Gly). The resulting fusion protein, DAB389SP-Gly, is composed of the catalytic and transmembrane domains of diphtheria toxin genetically coupled to SP-Gly. Because native SP requires a C-terminal amide moiety to bind with high affinity to the SP receptor, the precursor form of the fusion toxin, DAB389SP-Gly, was converted to DAB389SP by treatment with peptidylglycine-alpha-amidating monooxygenase. We demonstrate that following conversion, DAB389SP is selectively cytotoxic for cell lines that express either the rat or the human SP receptor. We also demonstrate that the cytotoxic action of DAB389SP is mediated via the SP receptor and dependent upon passage through an acidic compartment. To our knowledge, this is the first reported use of a neuropeptide as the targeting ligand for a fusion toxin; and the first instance in which an inactive precursor form of a fusion toxin is converted to the active form by a posttranslational modification. |
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Authors:
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C E Fisher; J A Sutherland; J E Krause; J R Murphy; S E Leeman; J C vanderSpek |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 93 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 1996 Jul |
Date Detail:
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Created Date: 1996-08-29 Completed Date: 1996-08-29 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 7341-5 Citation Subset: IM |
Affiliation:
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Evans Department of Clinical Research, Boston University Medical Center Hospital, Boston, MA 02118, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Base Sequence Binding, Competitive CHO Cells Cell Line Cell Survival / drug effects* Cloning, Molecular Cricetinae Diphtheria Toxin / biosynthesis*, toxicity* Escherichia coli Humans Kinetics Molecular Sequence Data Rats Receptors, Neurokinin-1 / biosynthesis, physiology* Recombinant Fusion Proteins / biosynthesis, toxicity Substance P / analogs & derivatives*, biosynthesis, metabolism, toxicity Transfection Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA 60934/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Diphtheria Toxin; 0/Receptors, Neurokinin-1; 0/Recombinant Fusion Proteins; 33507-63-0/Substance P; 98093-85-7/substance P, Gly(12)- |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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