Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin

Ras genes are commonly mutated in human cancers of the skin and other tissues. Oncogenic Ras signals through multiple effector pathways, including the Erk1/2 mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K) and the Ral guanine nucleotide exchange factor (RalGEF) cascades. In epidermis, the activation of oncogenic Ras induces hyperplasia and inhibits differentiation, features characteristic of squamous cell carcinoma. The downstream effector pathways required for oncogenic Ras effects in epidermis, however, are undefined. In this study, we investigated the direct contribution of Mek1 and Mek2 MAPKKs to oncogenic Ras signaling. The response of murine epidermis to conditionally active oncogenic Ras was unimpaired by deletion of either Mek1 or Mek2 MAPKKs individually. In contrast, Ras effects were entirely abolished by combined deletion of all Mek1/2 alleles, whereas epidermis retaining only one allele of either Mek1 or Mek2 showed intermediate responsiveness. Thus, the effects of oncogenic Ras on proliferation and differentiation in skin show a gene dosage-dependent requirement for the Erk1/2 MAPK cascade at the level of Mek1/2 MAPKKs.