PHOTODISC

The proteins encoded by the oncogenes KRAS and NRAS are highly homologous and have similar enzymatic functions, but mutations in KRAS are found in nearly 50% of human colon cancers, whereas only about 5% occur in NRAS. In their Nature Genetics paper, Tyler Jacks and colleagues used genetically engineered mice to shed light on the distinct effects of KRAS and NRAS in differentiation and tumorigenesis in colonic epithelium.

To investigate the effects of activating mutations in Kras and Nras in colonic epithelium, Jacks and colleagues created the first conditional activated allele of Nras (Nras^LSL-G12D), which, like the previously described Kras^G12D allele, can be expressed (using the Cre–Lox system) at wild-type levels from the endogenous locus. Whereas no effect on the histology of the colonic epithelium was observed on expression of NRAS^G12D, expression of KRAS^G12D led to widespread hyperplasia, but did not result in cancer. In the context of APC-null colonic tumours, KRAS^G12D led to uniformly high-grade dysplasia, without the areas of low-grade, well-differentiated cells that are observed in tumours with wild-type versions of KRAS and NRAS, or with mutant NRAS. These data indicate that, although activation of KRAS alone is insufficient to induce neoplasia in colonic epithelium, it can promote the progression of tumours arising from other mutations, and seems to suppress differentiation of colon cancer cells.

So which pathways mediate the effects of KRAS^G12D? The authors found that in a wild-type background KRAS^G12D can activate the mitogen-activated protein kinase kinase MEK, and the hyperplastic phenotype caused by Kras^G12D is hypersensitive to inhibition of MEK by CI-1040. However, CI-1040 did not affect the proliferation of any tumours that developed in APC-null KRAS^G12D-expressing animals. Instead, the authors went on to show that mutant KRAS-mediated activation of Raf might be important for tumour progression.

Although these findings indicate the pro-tumorigenic pathways mediated by KRAS, why are NRAS mutations sometimes seen? The authors found that NRAS^LSL-G12D promotes cell survival in response to specific apoptotic stimuli, a phenotype that might be selected for during the progression of some colon cancers.

Are the different phenotypes arising from mutations in Kras and Nras due to functional differences between the protein products, or simply the result of differing patterns of expression? The authors assert that the balance of evidence suggests the former, and that the unique ability of activated KRAS to signal through Raf is responsible for its selection in colon cancer.

Author: Isobel Barry