Endogenous locus-driven H-Ras G12V expression induces senescence-like phenotype in primary fibroblasts of the Costello syndrome mouse model

Oncogenic H-Ras germline mutations are associated with Costello syndrome (CS), a developmental disorder characterised by the failure to thrive, skin and musculoskeletal abnormalities, cardiomyopathy, and susceptibility to tumour development. Despite harbouring H-Ras oncogenic mutations, in both patients and a CS mouse model, the tumour incidence is very low. Using CS mouse primary fibroblasts, we identified that unlike the lack of tumorigenic transformation, the MAPK and Akt pathways display subtle changes in their activation kinetics. In vivo, these subtle changes might not be sufficient to induce malignant transformation, but may well be responsible for inducing CS pathologies. Moreover, we identified an oncogene-induced senescence-like phenotype, and we consider it as a potential mechanism in order to block tumour development in CS. The induction of oncogene-induced senescence-like phenotype can ultimately affect proliferative cells (e.g., progenitor cells) and impair tissue homeostasis during embryonic development and throughout the life span of CS patients.