Molecular mechanisms of oncogenesis mediated by the btb transcription factor pipsqueak: impact of sumoylation and proteolytic processing

• Autores: Verónica Miguela Fernández
• Directores de la Tesis: María Domínguez Castellano (dir. tes.), Esther Caparrós Cayuela (codir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2014
• Idioma: español
• Tribunal Calificador de la Tesis: Sonsoles Campuzano Corrales (presid.), Ana Carmena de la Cruz (secret.), Javier Sanz (voc.), Rosa Barrio Olano (voc.), Marco Milán Kalbfleisch (voc.)
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: RediUMH (pdf)
• Resumen

  • Cancer is a cellular phenomenon that occurs within the context of normal tissues and a normal microenvironment within the organism. Nowadays one of the major challenges regarding cancer is to understand how the oncogenic mechanisms confer malignant properties to the cells by altering the regulation of physiological tissue growth, the cessation of growth, cell differentiation, apoptosis and hormonal control. Over the past years, many works have linked the activity of numerous BTB transcription factors, such as PLZF or BCL-6, with human cancer. However, the molecular mechanisms that regulate their activity during oncogenesis remain poorly understood. In this Thesis I have used the Drosophila BTB transcription factor Pipsqueak as a paradigm to unravel new mechanisms of tumorigenesis mediated by BTB transcription factors. More specifically, I have focused on how sumoylation and proteolytic processing modulate Pipsqueak activity during normal development and oncogenesis. On the one hand, we have demonstrated that Pipsqueak sumoylation at Lysine 633 attenuates its transcriptional activity and its pro-apoptotic activity. The results presented in this Thesis suggest that sumoylation mediates the interaction of Pipsqueak with distinct proteins, such as the transcriptional repressor MEP-1 or the component of the basal transcriptional machinery DmTAF3, which are able to modulate the activity of this BTB transcription factor. On the other hand, we have found that the long PipsqueakB isoform is subjected to two mutually exclusive proteolytic events. We show that the two types of processing occur in different compartments of the cell, and specifically Type I processing is necessary for Pipsqueak transcriptional activity. We also demonstrate the responsible of this type of processing is the proteasome. The results of both studies offer new hints that will help us to better understand the complex molecular mechanisms underlying the regulation of the activity of BTB transcription factors.