Caracterización de la activación del oncogén K-ras V12 endógeno in vivo mediante una aproximación genética. Validación de Farnesiltransferasa en la terapia antitumoral in vivo mediante una aproximación genética
EntityUAM. Departamento de Biología Molecular
SubjectsOncogenes-Tesis doctorales; Biología y Biomedicina / Biología
NoteTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 26-04-2005
We have targeted a K-ras allele in mouse embryonic stem (ES) cells to express a KRasVl2 oncoprotein along with a marker protein (p-geo) from a single bicistronic transcript. Expression of this oncogenic allele requires removal of a knocked-in STOP transcriptional cassette by Cre recombinase. This mouse model will establish the experimental bases to study the wnsequences of K-ras activation within a physiological context. In vivo, most K-rasV12 oncogene expressing cells remain normal for long periods of time (up to eight months). Only, lung bmnchiolo-alveolar cells acquire hyper-proliferative propetties and progress into malignant adenocarcinomas. Cdk4 R24C mutation, which makes insensible to the 1NK4 inhibitor family members, cooperates with K-rasV12 mutation leading to the development of PanlN 1A metaplasias in pancreatic ductal cells and hyperplasias in pituitary cells. The K-rasVl2 driven adenocarcinomas acquire a spreading phenotype and thus develop metastads in the adjacent lymphoid nodules when wmbined with a p53 null background. In primary mouse embryonic fibroblasls (MEFs) activation of this K-rasVI2 onwgene at physiological level does not induce senescence due to oncogenic stress. Wñat is more. MEFs expressing this K-rasV12 allele proliferate as immortal cells and escape replicative senescence. Farnesyltransferase (FTase) is a heterodimeric enzyme responsible for post-translational modification of proteins carrying a carboxy-terminal CAAX motif. Farnesylation allows substrates, such as the Ras proteins involved in a significant fraction of human cancers, to interact with membranous structures and other protein targets. Using gene-targeted mice, we repott that FTase is essential for early embryonic development, but dispensable for adult homeostasis including responses to stress challenges. Older FTase mice display delayed wound healing and maturation defects in erythroid cells. FTase deficient embryonic fibroblasts have a distinct flat morphology and reduced motili, plating efficiency and proliferation rates. Ablation of FTase has no effect on tumor development induced by an endogenous K-ras oncogene. In a carcinogen-induced skin tumor model, loss of FTase results in decreased tumor progression, but has no effect on the activation of H-ras oncogenes. These results indicate that protein famesylation is not essential for the transformlng activtly of ras oncogenes.
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