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oai:gredos.usal.es:10366/1493412025-04-30T20:47:16Zcom_10366_4577com_10366_4576com_10366_3823com_10366_143089com_10366_123103com_10366_121440com_10366_4746col_10366_4585col_10366_143121col_10366_122452

Clavaín Mateo, Laura 2022-04-26T11:57:01Z 2022-04-26T11:57:01Z 2021 http://hdl.handle.net/10366/149341 [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. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Tesis y disertaciones académicas Universidad de Salamanca (España) Resumen de tesis Thesis Abstracts Mutations Ovarian cancer Proteins Tumor Resumen de tesis. Functional characterizacion of RRAS2 mutations and role of RRAS2Q72L in ovarian cancer info:eu-repo/semantics/doctoralThesis