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
Author
Mijimolle Cuadrado, NievesAdvisor
Barbacid, MarianoEntity
UAM. Departamento de Biología MolecularDate
2005-04-26Subjects
Oncogenes-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 26-04-2005Abstract
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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