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Título
Resumen de tesis. Functional characterizacion of RRAS2 mutations and role of RRAS2Q72L in ovarian cancer
Otros títulos
Functional characterizacion of RRAS2 mutations and role of RRAS2Q72L in ovarian cancer
Autor(es)
Director(es)
Palabras clave
Tesis y disertaciones académicas
Universidad de Salamanca (España)
Resumen de tesis
Thesis Abstracts
Mutations
Ovarian cancer
Proteins
Tumor
Clasificación UNESCO
2407 Biología Celular
32 Ciencias Médicas
3207.13 Oncología
Fecha de publicación
2021
Resumen
[EN] R-RAS2 is a small GTPase with high structural proximity to classical RAS proteins. RRAS2 gain-of-function mutations have been identified at low frecuency in recent PanCancer studies. However, the cancer driver and pathobiological roles of
this GTPase remain poorly characterized. In this thesis we have used in vitro and in
vivo models to tackle those issues. We have demonstrated that tumor-found RRAS2
mutations targeting residues involved in the GTP-binding are able to induce cell
transformation in vitro. Analyses of R-RAS2Q72L-expressing cancer cell lines have
shown that this protein in required for the tumoral fitness of the cells. In these cell
models, R-RAS2Q72L modulates pathways involved in cell proliferation and survival
and regulates basic processes such as polysomal translation and cell metabolism.
However, these effects are not driven by R-RAS2 expression. This work also exposes
a driver role for R-Ras2Q72L in tumorigenesis. The R-Ras 5$62Q72L-driven tumors exhibit
diffential sensitivity to mTORCI and/or P13K phamarcological inhibition, with
some tumors showing resistance to all the inhibitors tested. The characterization of the
R-Ras2Q72L-triggered ovarian cystadenomas has revealed a rete ovarii origin and a sexreversal phenotype in these tumors. Beyond tumorigenesis, R-Ras2Q72L also triggers
follicular atresia- and absent spermatogenesis-induced infertility in mice. Altogether,
oir findings unveil novel phatological functions of R-RAS2 and expand the current
knowledge of cellular functions of the wild-type and the oncogenic R-RAS2 versions.
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