Fragment A is catalytically active and mediates intracellular toxicity, while fragment B is responsible for receptor binding and internalization (Figure 2(a)). Please enable it to take advantage of the complete set of features! J Biol Chem 256: 1225–1228, Mekada E, Kohno K, Ishiura M, Uchida T, Okada Y (1982) Methylamine facilitates demonstration of specific uptake of diphtheria toxin by CHO cell and toxin-resistant CHO cell mutants. 260: 12148–12153, Mekada E, Uchida T, Okada Y (1981) Methylamine stimulates the action of ricin toxin but inhibits that of diphtheria toxin. Dadurch hemmt das Diphtherietoxin die Fähigkeit des eEF-2, die Translation der wachsenden Polypeptidkette auszuführen. The knock-in mouse is a RDS mouse, being characterized by that the human-derived diphtheria toxin receptor is inserted into the lysozyme M gene locus on the mouse genome. Diphtheria toxin is extraordinarily potent. Like the previous toxins discussed, DT ADP-ribosylates an intracellular target protein, for DT the elongation factor 2, which thereby becomes inactive, resulting in inhibition of cellular protein synthesis and cell death. Recombinant-DT-based ITs are constructed by mutating or replacing the carboxyl terminal cell binding domain of DT with a ligand or the Fv fragment of an antibody to a cancer cell surface receptor. (C, D) Whole mount images of hyaloid vessels in the eye showing scheduled loss of vasculature in the eye between P3 and P8 in wild-type mice. J Biol Chem 266: 5769–5773, Papini E, Schiavo G, Sandona D, Rappuoli R, Montecucco C (1989) Histidine 21 is at the NAD’ binding site of diphtheria toxin. The B subunit of DT binds to a specific receptor on the target cells, heparin-binding epidermal growth factor (HB-EGF). Diphtheria toxin kills cells by inhibiting eukaryotic protein synthesis, and its mechanism of action has been extensively characterized. − These proteins were called cross-reacting material (CRM) since they were immunologically cross-reactive with DT. Proc Natl Acad Sci USA 81: 3307–3311, Carroll SF, McCloskey JA, Crain PF, Oppenheimer NJ, Marschner TM, Collier RJ (1985) Photoaffinity labeling of diphtheria-toxin fragment A with NAD: structure of the photoproduct at position 148. Interestingly, the Pseudomonas aeruginosa exotoxin A has a very similar structure, but uses a different cell receptor: the α-2 macroglobulin low-density lipoprotein receptor. Transgenic expression of DTR selectively in one of a restricted number of cell types can yield a mouse in which injection of DT into the circulation results in uptake of the DTA subunit only into cells expressing the transgene and rapid loss or ablation of the specific cell-type [30,36–39]. Cell 69: 1051–1061, Nakagawa T, Higashiyama S, Mitamura T, Mekada E, Taniguchi N (1996) Amino-terminal processing of cell surface heparin-binding epidermal growth factor-like growth factor up-regulates its juxtacrine but not its paracrine growth factor activity. Chromosoma 96: 26–32, Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M (1991) A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. These mice have been used to study the effects of DT on specific cell types as well as models for development and disease. Showalter, Degradable, poly(β-amino ester) polymer, poly(butane diol diacrylate co-amino pentanol) (C32), DTA driven by a prostate-specific promoter, Benign prostatic hyperplasia (BPH) and prostate cancer. The A and B fragments of DT are depicted with the T domain (contained in the B fragment) shown as a green diamond. We use cookies to help provide and enhance our service and tailor content and ads. Allerdings sind die toxischen Mechanismen dieser Toxine unterschiedlich. + DT causes local tissue destruction and results in immune cell influx, causing formation of the pseudomembrane in the throat. [2], NAD Since EF-2 is present in low concentrations and has a slow turnover, one molecule of DT is predicted to halt the entire cellular population of EF-2, resulting in complete termination of cellular protein synthesis. eEF DTA under the control of human AFP promoter/enhancer directed to AFP-producing hepatocellular carcinoma cells (using cationic liposomes (DMRIE-C)). The tox gene is encoded by a phage and is under the control of the repressor protein DtxR, which forms an iron complex, DtxR-Fe (Figure 2-11), that binds DNA and represses tox expression. tumor). new endogenous transport receptor for the delivery of drags across the BBB. The receptor was identified by its ability to confer toxin-sensitivity to mouse cells, which are normally toxin-resistant. The use of these systems was first reported by Evans in 1989, and Breitman in 1990 [33,40,41]. Diphtheria toxin was the first member to be identified of a group of bacterial protein toxins that act by ADP-ribosylation of a target protein. 2002 Dec;20(12):1234-9. doi: 10.1038/nbt762. Mallet VO, Mitchell C, Guidotti JE, Jaffray P, Fabre M, Spencer D, Arnoult D, Kahn A, Gilgenkrantz H. Nat Biotechnol. We expressed the diphtheria toxin (DT) receptor in transgenic mice using a hepatocyte-specific promoter and found that injection of DT caused fulminant hepatitis.

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