title: Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF.
abstract: KRAS and BRAF are among the most commonly mutated oncogenes in human cancer that contribute to tumorigenesis in both distinct and overlapping tissues. However, KRAS and BRAF mutations are mutually exclusive; they never occur in the same tumor cell. The reason for the mutual exclusivity is unknown, but there are several possibilities. The two mutations could be functionally redundant and not create a selective advantage to tumor cells. Alternatively, they could be deleterious for the tumor cell and induce apoptosis or senescence. To distinguish between these possibilities, we activated the expression of BRAF(V600E) and KRAS(G12D) from their endogenous promoters in mouse lungs. Although the tumor-forming ability of BRAF(V600E) was higher than KRAS(G12D), KRAS(G12D) tumors were larger and more advanced. Coactivation of BRAF(V600E) and KRAS(G12D) markedly reduced lung tumor numbers and overall tumor burden compared with activation of BRAF(V600E) alone. Moreover, several tumors expressed only one oncogene, suggesting negative selection against expression of both. Similarly, expression of both oncogenes in mouse embryonic fibroblasts essentially stopped proliferation. The expression of both oncogenes hyperactivated the MEK-ERK-cyclin D pathway but reduced proliferation by increasing the production of p15, p16 and p19 proteins encoded by the Ink4/Arf locus and thereby increased senescence-associated β-galactosidase-positive cells. The data suggest that coexpression of BRAF(V600E) and KRAS(G12D) in early tumorigenesis leads to negative selection due to oncogene-induced senescence.
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Cancer Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Cisowski
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Cancer Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.|Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: V I
authors.initials: VI
authors.lastname: Sayin
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Cancer Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Cancer Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: D048493:Proto-Oncogene Proteins B-raf; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)