Post-transcriptional determinants of ras protein abundance

• Autores: Hannah Benisty Sánchez Elvira
• Directores de la Tesis: Luis Serrano Pubull (dir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Eduardo Batlle Gomez (presid.), Eva María Novoa Pardo (secret.), Santiago Ramón y Cajal Junquera (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Física
    • Física molecular
      • Estructura molecular
  • Química
    • Bioquímica
      • Proteínas
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• Resumen

  • In the early 1980s, RAS genes were identified as oncogenes. The point mutation responsible for the transforming properties of RAS was found later in 1982 in a human cancer cell line. This was reported by the Weinberg, Barbacid and Wigler groups. Subsequently, the cancer field started buzzing with the discovery of RAS oncogenes, which marked a shift in human cancer research. The RAS oncogenes −KRAS, NRAS and HRAS− are mutated in one third of human cancers where they exhibit different mutation patterns. Nevertheless, one of the most intriguing clinical observations remains unsolved: Why are KRAS mutations much more frequent in human cancer compared to NRAS or HRAS mutations? This observation is surprising because the three forms are nearly identical, each of them is capable of cell transformation in different model systems, and, all forms are widely expressed across tissues. In addition, the underlying reasons for the different frequencies of each type of substitution of activating mutations are yet to be fully elucidated. A potential factor contributing to this mutation bias is the variation of RAS expression levels. Here, I investigate some of the determinants of RAS protein abundance. First, I examine whether codon bias among RAS genes and within other cancer gene families plays a role in cell context-specific expression. I further describe a tRNA expression program that favors oncogene translation in proliferating cells. Second, I investigate why oncogenic RAS mutants exhibit a higher protein abundance than the RAS wild type. In this context, I study the underlying mechanisms leading to this variation and more specifically how protein-protein interactions between RAS and its downstream binding partners change the protein turnover of RAS and therefore, its protein abundance. Overall, this thesis provides insight into the possible relevance of RAS protein synthesis and protein degradation as determinants of RAS mutation patterns in human cancers.