Congruent with mouse models (Schuhmacher et al., 2008), ERK1/2 and Akt phosphorylation were not upregulated in HRASG12V transgenic zebrafish and remain unlikely drivers of CS pathology; rather, the ability of HRAS to induce hyperproliferation, DNA damage, and cellular senescence through the DNA damage response (DDR) is a well-documented cause (Di Micco et al., 2006). This evidence concerns the gene HRAS and Cowden syndrome 1.