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1. Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development.

Author

Mijimolle N, Velasco J, Dubus P, Guerra C, Weinbaum CA, Casey PJ, Campuzano V, and Barbacid M

Subjects
Alkyl and Aryl Transferases genetics, Alkyl and Aryl Transferases metabolism, Animals, Cell Proliferation, Embryo Loss genetics, Embryo Loss pathology, Embryo, Mammalian metabolism, Embryo, Mammalian pathology, Embryonic Development genetics, Erythroid Cells enzymology, Erythroid Cells pathology, Estrogen Antagonists pharmacology, Fibroblasts enzymology, Fibroblasts pathology, Gene Expression drug effects, Gene Expression genetics, Integrases genetics, Liver enzymology, Liver pathology, Lung enzymology, Lung pathology, Mice, Mice, Knockout, Mutation genetics, Neoplasms genetics, Neoplasms pathology, Skin Neoplasms enzymology, Skin Neoplasms genetics, Skin Neoplasms pathology, Spleen pathology, Tamoxifen pharmacology, Wound Healing genetics, Wound Healing physiology, ras Proteins genetics, ras Proteins metabolism, Alkyl and Aryl Transferases physiology, Embryonic Development physiology, Homeostasis physiology, Neoplasms enzymology, Tamoxifen analogs & derivatives
Abstract

Protein farnesyltransferase (FTase) is an enzyme responsible for posttranslational modification of proteins carrying a carboxy-terminal CaaX motif. Farnesylation allows substrates to interact with membranes and protein targets. Using gene-targeted mice, we report that FTase is essential for embryonic development, but dispensable for adult homeostasis. Six-month-old FTase-deficient mice display delayed wound healing and maturation defects in erythroid cells. Embryonic fibroblasts lacking FTase have a flat morphology and reduced motility and proliferation rates. Ablation of FTase in two ras oncogene-dependent tumor models has no significant consequences for tumor initiation. However, elimination of FTase during tumor progression had a limited but significant inhibitory effect. These results should help to better understand the role of protein farnesylation in normal tissues and in tumor development.

Published
2005
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2. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context.

Author

Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, Campuzano V, and Barbacid M

Subjects
Animals, Cell Division, Cell Line, Transformed, Cellular Senescence, Chromosome Aberrations, Cyclin-Dependent Kinase Inhibitor p16, Fibroblasts metabolism, Gene Targeting, Genetic Vectors genetics, MAP Kinase Signaling System, Mice, Mice, Transgenic, Oncogene Protein p21(ras) genetics, Oncogene Protein p21(ras) metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells pathology, Survival Rate, Tumor Suppressor Protein p14ARF genetics, Tumor Suppressor Protein p14ARF metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Cell Transformation, Neoplastic, Fibroblasts pathology, Genes, ras genetics, Neoplasms genetics, Neoplasms pathology, Protein Serine-Threonine Kinases
Abstract

We have targeted a K-ras allele in mouse embryonic stem (ES) cells to express a K-Ras(V12) oncoprotein along with a marker protein (beta-geo) from a single bicistronic transcript. Expression of this oncogenic allele requires removal of a knocked in STOP transcriptional cassette by Cre recombinase. Primary mouse embryonic fibroblasts expressing this K-ras(V12) allele do not undergo proliferative senescence and proliferate as immortal cells. In mice, expression of K-ras(V12) throughout the body fails to induce unscheduled proliferation or other growth abnormalities for up to eight months. Only a percentage of K-ras(V12)-expressing lung bronchiolo-alveolar cells undergo malignant transformation leading to the formation of multiple adenomas and adenocarcinomas. These results indicate that neoplastic growth induced by an endogenous K-ras oncogene depends upon cellular context.

Published
2003
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