Danger zone

Abstract

What level of Ras genes activity leads to the development of cancer?

Keywords: RAS; cancer biology; carcinogenesis; codon bias; mouse; oncogenesis; tumor initiation; tumour initiation.

Figure 1.. Optimal Ras signalling is required for tumour development.

Li and Counter investigated the impact of Q61* and G12* mutations in the Ras gene KRAS on wild-type and mutant mice. Q61* and G12* mutations respectively lead to a large and moderate increase in the activity of the gene. Wild-type mice exposed to urethane (which causes Q61* mutations) develop lung cancer after a year (top; first line of table). KRAS^ex3op mutant mice have raised Ras activity, and therefore increased oncogenic stress; in these animals, the G12* mutation is the main driver of tumours, because it is less active than Q61* (second line of table). Conversely, p53^-/- mice have decreased oncogenic stress and are able to tolerate high levels of Ras activity driven by Q61* mutations, leading to tumour growth; however, they also showed increased levels of G12* KRAS mutant messenger RNA (third line). p53^-/-, KRAS^ex3op mutants have normal levels of oncogenic stress, and in these animals both Q61* and G12* mutation can lead to disease (fourth line). Overall, depending on the genetic background of the animal, which mutations lead to the level of Ras activity that triggers cancer varies (bottom). ↑ indicate genotypes or post-transcriptional mechanisms that increase Ras abundance.