Papel de la serina treonina quinasa "altered disjunction (ald)" en la regulación de la integridad epitelial y progresión tumoral

• Autores: Beatriz Pérez San Juan
• Directores de la Tesis: Antonio Baonza Cuenca (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
• Idioma: español
• Tribunal Calificador de la Tesis: Sonsoles Campuzano Corrales (presid.), Luis Alberto Baena López (secret.), Natalia Azpiazu Torres (voc.), Fernando Roch (voc.), Maria Rosa Barrio Olano (voc.)
• Menciones:
  • Europea
• Calificación: Apto Cum Laude
• Materias:
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Mps1 (Mono-polar spindle 1) is an evolutionary conserved serine treonine kinase that regulates normal mitotic progression and the spindle checkpoint in response to stress. Changes in Mps1 protein levels have been related with the development of cancer in human. This tumor-promoting function it¿s been attributed to the chromosomal instability observed when the activity of this kinase is modified. However, other functions of this kinase involved in tumor progression still remain unknown. We have analyzed the function of the Drosophila melanogaster Mps1 homologue, altered disjunction (ald).

    Our data indicate that ald activity alteration can contribute to the tumour formation and progression by different mechanims.

    Firstly, ald deregulation in different imaginal discs causes alteration of the components of the adherents junctions and the disruption of the apico-basal polarity domains, compromising the epithelial integrity. Indicating that the function of ald is required for the definition and/or maintenance of the epithial tissue arquitecture. The lack of epithelial integrity induced by both, gain and loss of function of ald, caused changes in the properties of the mutant epithelial cells. Thus, cells that over-express Ald undergo a pseudo epithelial to mesenchimal transition (EMT) and acquire cell motility and invasiveness propierties. We have found that Ald mediates part of these effects by regulating Moesin, Rho1 and the JNK signalling. Furthermore, this effect it is enhanced by the combination with RasV12 and Notchintra oncogenes. Moreover, our observation indicate that ald mutant epithelium is sensitive to changes in the levels of other tumour suppressor genes, such as lethal giant larvae (lgl), as indicate that double mutant ald/lgl epithelium massively overgrowth when the larvae are raised at restrictive metabolic condition.

    Secondly, we have identified a new role for this kinase, preventing mitotic recombination in the somatic cells. Mitotic recombination is a rare event caused by failure in DNA damage response and repair mechanisms. This incident can produce loss of heterozygosity (LOH), a process that can be very deleterious for the organism and increased susceptibility to the development of tumour. In ald mutant flies we observed that the frequency of mitotic recombination was strongly increased. As consequence of this defect we have found that flies heterozigous for mutations on tumor suppressor genes, frequently develop clones of mutant cells for these genes that can overgrowth.

    Indicating the high susceptibility of these flies to develop tumors .

    In summary, our work uncovered novel functions for this kinase that could help to understand its contribution to the biogenesis and tumor progression.