Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
| Autor: | Pierre Dubus, Roco Sotillo, Mariano Barbacid, Javier Martn, Ernesto de la Cueva, Marcos Malumbres, Sagrario Ortega |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Male
Time Factors Lymphoma Mutant Cell Cycle Proteins Mice Tumor Suppressor Protein p14ARF Hereditary Melanoma Melanoma Mice Knockout Recombination Genetic biology Kinase General Neuroscience Cell Cycle Homozygote Teratoma Sarcoma 3T3 Cells Exons Penetrance Cyclin-Dependent Kinases Gene Expression Regulation Neoplastic Female Cyclin-Dependent Kinase Inhibitor p27 Blotting Western Molecular Sequence Data General Biochemistry Genetics and Molecular Biology Article Sex Factors Transformation Genetic Cyclin-dependent kinase Gene knockin Proto-Oncogene Proteins Animals Humans Point Mutation Genetic Predisposition to Disease Molecular Biology Alleles Cyclin-Dependent Kinase Inhibitor p16 General Immunology and Microbiology Cyclin-dependent kinase 4 Point mutation Tumor Suppressor Proteins Cyclin-Dependent Kinase 4 Fibroblasts Genes p53 Molecular biology Precipitin Tests Genes ras Protein Biosynthesis Mutation biology.protein Cancer research |
| Popis: | We have introduced a point mutation in the first coding exon of the locus encoding the cyclin-dependent kinase 4 (Cdk4) by homologous recombination in embryonic stem cells. This mutation (replacement of Arg24 by Cys) was first found in patients with hereditary melanoma and renders Cdk4 insensitive to INK4 inhibitors. Here, we report that primary embryonic fibroblasts expressing the mutant Cdk4R24C kinase are immortal and susceptible to transformation by Ras oncogenes. Moreover, homozygous Cdk4(R24C/R24C) mutant mice develop multiple tumors with almost complete penetrance. The most common neoplasia (endocrine tumors and hemangiosarcomas) are similar to those found in pRb(+/-) and p53(-/-) mice. This Cdk4 mutation cooperates with p53 and p27(Kip1) deficiencies in decreasing tumor latency and favoring development of specific tumor types. These results provide experimental evidence for a central role of Cdk4 regulation in cancer and provide a valuable model for testing the potential anti-tumor effect of Cdk4 inhibitors in vivo. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|