Human diploid fibroblasts are resistant to MEK/ERK-mediated disruption of the actin cytoskeleton and invasiveness stimulated by Ras

Ras-induced transformation is characterized not only by uncontrolled proliferation but also by drastic morphological changes accompanied by the disruption of the actin cytoskeleton. Previously, we reported that human fibroblasts are more resistant than rodent fibroblasts to Ras-induced transformation. To explore the molecular basis for the difference in susceptibility to Ras-induced transformation, we investigated the effect of activated H-Ras on the actin cytoskeleton in human diploid fibroblasts and in rat embryo fibroblasts, both of which are immortalized by SV40 early region. We demonstrate here that Ras-induced morphological changes, decreased expression of tropomyosin isoforms, and suppression of the ROCK/LIMK/Cofilin pathway observed in the rat fibroblasts were not detected in the human fibroblasts even with high expression levels of Ras. We also show that activation of the MEK/ERK pathway sufficed to induce all of these alterations in the rat fibroblasts, whereas the human fibroblasts were refractory to these MEK/ERKmediated changes. In addition to morphological changes, we demonstrated that the expression of activated Ras induced an invasive phenotype in the rat, but not in the human fibroblasts. These studies provide evidence for the existence of human-specific mechanisms that resist Ras/MEK/ERK-mediated transformation.