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Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL

Schorch, Björn; Heni, Hannah; Zahaf, Nour Imene; Brummer, Tilman; Mione, Maria Caterina; Schmidt, Gudula; Papatheodorou, Panagiotis; Aktories, K.

Abstract (englisch):

Clostridium perfringens toxin TpeL belongs to the family of large clostridial glycosylating toxins. The toxin causes N-acetylglucosaminylation of Ras proteins at threonine35 thereby inactivating the small GTPases. Here, we show that all main types of oncogenic Ras proteins (H-Ras, K-Ras and N-Ras) are modified by the toxin in vitro and in vivo. Toxin-catalyzed modification of Ras was accompanied by inhibition of the MAP kinase pathway. Importantly, TpeL inhibited the paradoxical activation of the MAP kinase pathway induced by the BRAF inhibitor Vemurafenib in the human melanoma cell line SBCL2. The toxin also blocked Ras signaling in a zebrafish embryo model expressing oncogenic H-Ras$^{G12V}$, resulting in a reduction of melanocyte number. By using the binding and translocation component of anthrax toxin (protective antigen), the glucosyltransferase domain of TpeL was effectively introduced into target cells that were not sensitive to native TpeL toxin. To reach a higher specificity towards cancer cells, a chimeric TpeL toxin was engineered that possessed the knob region of adenovirus serotype 35 fiber, which interacts with CD46 of target cells frequently overexpressed in cancer cells. ... mehr


Verlagsausgabe §
DOI: 10.5445/IR/1000082248
Veröffentlicht am 12.11.2018
Originalveröffentlichung
DOI: 10.18632/oncotarget.24740
Scopus
Zitationen: 11
Dimensions
Zitationen: 10
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsmonat/-jahr 03.2018
Sprache Englisch
Identifikator ISSN: 1949-2553
urn:nbn:de:swb:90-822486
KITopen-ID: 1000082248
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in OncoTarget
Verlag Impact Journals
Band 9
Heft 23
Seiten 16489-16500
Vorab online veröffentlicht am 27.03.2018
Nachgewiesen in Scopus
Dimensions
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