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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bankston, Laurie A. Liddington, Robert C. Chen, Kuang-hua Liu, Shihui Leppla, Stephen H. |
| Description | Author Affiliation: Chen KH ( Laboratory of Bacterial Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-3202, USA.) |
| Abstract | Anthrax toxin, a three-component protein toxin secreted by Bacillus anthracis, assembles into toxic complexes at the surface of receptor-bearing eukaryotic cells. The protective antigen (PA) protein binds to receptors, either tumor endothelial cell marker 8 (TEM8) or CMG2 (capillary morphogenesis protein 2), and orchestrates the delivery of the lethal and edema factors into the cytosol. TEM8 is reported to be overexpressed during tumor angiogenesis, whereas CMG2 is more widely expressed in normal tissues. To extend prior work on targeting of tumor with modified anthrax toxins, we used phage display to select PA variants that preferentially bind to TEM8 as compared with CMG2. Substitutions were randomly introduced into residues 605-729 of PA, within the C-terminal domain 4 of PA, which is the principal region that contacts receptor. Candidates were characterized in cellular cytotoxicity assays with Chinese hamster ovary (CHO) cells expressing either TEM8 or CMG2. A PA mutant having the substitutions R659S and M662R had enhanced specificity toward TEM8-overexpressing CHO cells. This PA variant also displayed broad and potent tumoricidal activity to various human tumor cells, especially to HeLa and A549/ATCC cells. By contrast, the substitution N657Q significantly reduced toxicity to TEM8 but not CMG2-overexpressing CHO cells. Our results indicate that certain amino acid substitutions within PA domain 4 create anthrax toxins that selectively kill human tumor cells. The PA R659S/M662R protein may be useful as a therapeutic agent for cancer treatment. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 13 |
| Volume Number | 282 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2007-03-30 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antigenic Variation Antigens, Bacterial Genetics Metabolism Bacterial Toxins Membrane Proteins Neoplasm Proteins Receptors, Cell Surface Amino Acid Sequence Amino Acid Substitution Animals Chemistry CHO Cells Cell Line Cell Line, Tumor Cricetinae Cricetulus HeLa Cells Molecular Sequence Data Protein Structure, Tertiary Receptors, Peptide Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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