H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences

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...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2017-02, Vol.77 (3), p.707-718
Main Authors: Drosten, Matthias, Simón-Carrasco, Lucía, Hernández-Porras, Isabel, Lechuga, Carmen G, Blasco, María T, Jacob, Harrys K C, Fabbiano, Salvatore, Potenza, Nicoletta, Bustelo, Xosé R, Guerra, Carmen, Barbacid, Mariano
Format: Article
Language:English
Subjects:
Animals
Cancer
Disease Models, Animal
Embryo fibroblasts
Embryos
Genes, ras - genetics
H-Ras protein
Immunoblotting
Immunohistochemistry
K-Ras protein
Kinases
Lesions
Lethality
Lungs
MAP kinase
Mice
Mice, Transgenic
Neoplasms - genetics
Oncoproteins
Proteins
Quantitative analysis
ras Proteins - genetics
ras Proteins - metabolism
Regulatory sequences
Regulatory Sequences, Nucleic Acid
Rodents
Senescence
Tumor cells
Tumors
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Summary: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-Ras oncogene sequences. Germline expression of H-Ras or K-Ras from the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes. Whereas H-Ras elicited papillomas and hematopoietic tumors, K-Ras induced lung tumors and gastric lesions. Pulmonary expression of H-Ras created a senescence-like state caused by excessive MAPK signaling. Likewise, H-Ras but not K-Ras induced senescence in mouse embryonic fibroblasts. Label-free quantitative analysis revealed that minor differences in H-Ras expression 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-16-2925