Repurposing a Prokaryotic Toxin-Antitoxin System for the Selective Killing of Oncogenically Stressed Human Cells
| Autor: | Guillermo de la Cueva-Méndez, Mark A. Preston, Alice Turnbull, Camino Bermejo-Rodríguez, Isabelle Dionne, Belén Pimentel |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Genetic enhancement Bacterial Toxins Biomedical Engineering Uterine Cervical Neoplasms Apoptosis Biology Biochemistry Genetics and Molecular Biology (miscellaneous) Microbiology 03 medical and health sciences Bacterial Proteins Escherichia coli Humans Polyubiquitin Repurposing Cell Proliferation General Medicine Oncogene Proteins Viral Toxin-antitoxin system Recombinant Proteins Cell biology DNA-Binding Proteins Repressor Proteins 030104 developmental biology HEK293 Cells Female Antitoxins Antitoxin Genetic Engineering Intracellular Function (biology) |
| Zdroj: | ACS synthetic biology. 5(7) |
| ISSN: | 2161-5063 |
| Popis: | Prokaryotes express intracellular toxins that pass unnoticed to carrying cells until coexpressed antitoxin partners are degraded in response to stress. Although not evolved to function in eukaryotes, one of these toxins, Kid, induces apoptosis in mammalian cells, an effect that is neutralized by its cognate antitoxin, Kis. Here we engineered this toxin-antitoxin pair to create a synthetic system that becomes active in human cells suffering a specific oncogenic stress. Inspired by the way Kid becomes active in bacterial cells, we produced a Kis variant that is selectively degraded in human cells expressing oncoprotein E6. The resulting toxin-antitoxin system functions autonomously in human cells, distinguishing those that suffer the oncogenic insult, which are killed by Kid, from those that do not, which remain protected by Kis. Our results provide a framework for developing personalized anticancer strategies avoiding off-target effects, a challenge that has been hardly tractable by other means thus far. |
| Databáze: | OpenAIRE |
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