Cancer Research Center Research Center del Cancer
PubMed | CSIC - National Center for Metallurgical Research, Cancer Research Center Research Center del Cancer, University of Geneva, University of Naples and Spanish National Cancer Research Center
Type: | Journal: Cancer research | Year: 2016
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 bioequivalency of oncogenic H-Ras and K-Ras, we replaced the coding region of the murine K-Ras locus with H-RasG12V oncogene sequences. Germline expression of H-RasG12V or K-RasG12V from the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes. Whereas H-RasG12V elicited papillomas and hematopoietic tumors, K-RasG12V induced lung tumors and gastric lesions. Pulmonary expression of H-RasG12V created a senescence-like state caused by excessive MAP kinase signaling. Likewise, H-RasG12V but not K-RasG12V induced senescence in mouse embryo fibroblasts. Label-free quantitative analysis revealed that minor differences in H-RasG12V expression levels led to drastically different biological outputs, suggesting that subtle differences in MAP kinase signaling confer non-equivalent functions that influence tumor spectra induced by RAS oncoproteins.