Molecular mechanism of PE5-induced cytotoxicity and generation of new cytotoxic nuclear-directed
Cytotoxic ribonucleases are promising agents to be used in the treatment of cancer. Our group previously described a cytotoxic human pancreatic ribonuclease variant, named PE5, which carries a nuclear localization signal. This protein is routed into the nucleus, where it cleaves nuclear RNA inducing...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/283575 |
| Acceso en línea: | http://hdl.handle.net/10803/283575 |
| Access Level: | acceso abierto |
| Palabra clave: | Human pancreatic ribonuclease Ribonucleasa pancreàtica humana Ribonucleasa pancreática humana Nuclear delivery Localització nuclear Localización nuclear Cytotoxicity Citotoxicitat Citotoxicidad Protein engineering Enginyeria de proteïnes Ingeniería de proteínas Antitumor drugs Drogues antitumorals Drogas antitumorales Microarray Xip Chip 577 |
| Sumario: | Cytotoxic ribonucleases are promising agents to be used in the treatment of cancer. Our group previously described a cytotoxic human pancreatic ribonuclease variant, named PE5, which carries a nuclear localization signal. This protein is routed into the nucleus, where it cleaves nuclear RNA inducing the apoptosis of cancer cells. In the present work, the molecular mechanism of PE5-induced cytotoxicity has been investigated using global gene expression and miRNA microarrays. The results indicate that this ribonuclease causes pleiotropic effects and regulates the expression of numerous genes and miRNAs. On the other hand, we have improved the antitumor properties of PE5. First, we have obtained PE10, which is as cytotoxic as PE5 but it is potentially less immunogenic because its sequence is more similar to that of the wild type human pancreatic ribonuclease. And second, we have obtained NLSPE5, which exhibits 6-14 times higher cytotoxicity for tumor cells than PE5 |
|---|