The link between the centrosome, TSC disease and epithelial differentiation

• Autores: Laia Gómez Baldó
• Directores de la Tesis: Miguel Angel Pujana Genestar (dir. tes.), Víctor Moreno Aguado (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2010
• Idioma: inglés
• Tribunal Calificador de la Tesis: Javier Abel Menéndez Menéndez (presid.), José Luis Rosa López (secret.), Eduard Serra Arenas (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
  • Ciencias médicas
    • Patología
      • Carcinogénesis
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • Studies of the role of tuberous sclerosis complex (TSC) proteins (TSC1/TSC2) in pathology have focused mainly on their capacity to regulate translation and cell growth, but their relation with alterations of cellular structures and the cell cycle is not yet fully understood. The transforming acidic coiled-coil (TACC) domain-containing proteins are central players in structures and processes involving the microtubule network. Here, TACC3 interactome mapping identified TSC2 and 15 other proteins, including TACC homo and heterodimers, and two evolutionary conserved interactors (ch-TOG/CKAP5 and FAM161B). TACC3 and TSC2 co-localize and co-purify with components of the nuclear envelope, and their deficiency causes morphological alterations of this structure. During cell division, TACC3 is necessary for the proper localization of phospho-Ser939 TSC2 at the spindle poles and cytokinetic bridges. Consistently, abscission alterations and increased frequency of binucleated cells were observed in Tacc3- and Tsc2-deficent cells relative to controls. In regulating cell division, TSC2 acts epistatic to TACC3 and, in addition to canonical TSC/mTOR signaling and cytokinetic associations, converges to the early mitotic checkpoint mediated by CHFR. Our findings link TACC3 to novel structural and cell division functions of TSC2, which may provide additional explanations of the clinical and pathological manifestations of lymphangioleiomyomatosis disease and TSC syndrome, including the greater clinical severity associated with TSC2 germline mutations relative to TSC1.