title: H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences.
abstract: Genetic studies in mice have provided evidence that H-Ras and K-Ras proteins are bioequivalent. However, human tumors display marked differences in the association of RAS oncogenes with tumor type. Thus, to further assess the bioequivalence of oncogenic H-Ras and K-Ras, we replaced the coding region of the murine K-Ras locus with H-RasG12Voncogene sequences. Germline expression of H-RasG12Vor K-RasG12Vfrom the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes. Whereas H-RasG12Velicited papillomas and hematopoietic tumors, K-RasG12Vinduced lung tumors and gastric lesions. Pulmonary expression of H-RasG12Vcreated a senescence-like state caused by excessive MAPK signaling. Likewise, H-RasG12Vbut not K-RasG12Vinduced senescence in mouse embryonic fibroblasts. Label-free quantitative analysis revealed that minor differences in H-RasG12Vexpression levels led to drastically different biological outputs, suggesting that subtle differences in MAPK signaling confer nonequivalent functions that influence tumor spectra induced by RAS oncoproteins. Cancer Res; 77(3); 707-18. ©2016 AACR.
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. mdrosten@cnio.es mbarbacid@cnio.es.
authors.forename: Matthias
authors.initials: M
authors.lastname: Drosten
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Simón-Carrasco
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández-Porras
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Lechuga
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Blasco
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Harrys K C
authors.initials: HK
authors.lastname: Jacob
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Salamanca, Spain.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fabbiano
authors.affiliation: Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Second University of Naples, Caserta, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Potenza
authors.affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Salamanca, Spain.
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. mdrosten@cnio.es mbarbacid@cnio.es.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D011905:Genes, ras / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018631:ras Proteins