title: Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging.
abstract: Mammalian genes frequently present allelic variants that differ in their expression levels and that, in the case of tumor suppressor genes, can be of relevance for cancer susceptibility and aging. We report here the characterization of a novel mouse model with increased activity for the Ink4a and Arf tumor suppressors. We have generated a "super Ink4a/Arf" mouse strain carrying a transgenic copy of the entire Ink4a/Arf locus. Cells derived from super Ink4a/Arf mice have increased resistance to in vitro immortalization and oncogenic transformation. Importantly, super Ink4a/Arf mice manifest higher resistance to cancer compared to normal, nontransgenic, mice. Finally, super Ink4a/Arf mice have normal aging and lifespan. Together, these results indicate that modest increases in the activity of the Ink4a/Arf tumor suppressor result in a beneficial cancer-resistant phenotype without affecting normal viability or aging.
authors.affiliation: Spanish National Cancer Center (CNIO), Madrid E-28029, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.forename: Cristina
authors.initials: C
authors.lastname: Pantoja
authors.forename: Alejo
authors.initials: A
authors.lastname: Efeyan
authors.forename: Luis M
authors.initials: LM
authors.lastname: Criado
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Peter
authors.initials: P
authors.lastname: Klatt
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015127:9,10-Dimethyl-1,2-benzanthracene