Molecular mechanism of PE5-induced cytotoxicity and generation of new cytotoxic nuclear-directed

• Autores: Anna Vert Company
• Directores de la Tesis: Maria Vilanova Brugués (dir. tes.), Antoni Benito Mundet (dir. tes.)
• Lectura: En la Universitat de Girona ( España ) en 2014
• Idioma: inglés
• Tribunal Calificador de la Tesis: Claudi Cuchillo Foix (presid.), Mercè Figueras i Vall-llosera (secret.), Francesc Canals Suris (voc.)
• Materias:
  • Química
    • Bioquímica
      • Enzimología
      • Proteínas
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • 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