University of California, San Francisco, USA
A cancer geneticist delves into family matters.
A mystery lies at the heart of a small family of growth signalling enzymes (K-Ras, H-Ras and N-Ras), which are widely mutated in human cancers. In culture, all three enzymes have similar functions, but different ras genes are associated with cancers in different tissues.
My laboratory, for instance, noted more than 25 years ago that skin cancers show activation of H-ras. Others have demonstrated that lung, colon and pancreatic cancers show activation of K-ras, whereas N-ras is the oncogene of choice in melanomas and some leukaemias.
What determines this intriguing specificity? Are the enzymes’ functions somehow modified in certain tissues in vivo? Or is it regulation of the genes, affecting where and when they are expressed, that matters?
We may get some answers by following the lead of an elegant study (N. Potenza et al. EMBO Rep. 6, 432–437; 2005). In this work, the authors knocked out K-ras in mice, but simultaneously replaced the gene with its close relative H-ras, doctored to have the regulatory elements of K-ras. Mice can survive without the H-ras or N-ras genes (or even both of them) but usually die if K-ras is deleted. These mice, despite lacking K-ras, were viable and lived to a ripe old age.
This important observation provides novel opportunities to probe the mechanisms of cancer initiation. Are the mice lacking K-ras now resistant to the lung and pancreatic cancers that are normally linked to K-ras? If yes, this would indicate a true requirement for the K-Ras protein in lung-cancer development; if not, the focus would switch to regulation.
A straw poll of Ras cognoscenti suggests that opinion is for now divided, but my group and others are working on this mouse model, and hope to have answers soon.