Ras Participates in the Regulation of the Stability of Adenoviral Protein E1A via MAP-kinase ERK.

The E1A adenoviral protein required for the initiation of the viral life cycle is being actively studied as a sensitizing agent in the combination therapy of cancer, and tumors with activated Ras in particular. We investigated the role played by the Ras signaling pathway in the regulation of E1A protein stability and showed that overexpression of activated Ras increases the basal level of E1A, but enhances the degradation of the E1A protein under treatment with histone deacetylase inhibitors (HDIs). It has been found that the MAP kinase ERK is the key factor in E1A stabilization, and ERK inactivation upon HDI treatment reduces the E1A protein level. Our results indicate that the combination treatment of tumors with activated Ras using adenoviral E1A and HDI has limitations attributed to intense HDI-dependent degradation of E1A. Nevertheless, the established contribution of ERK kinase to the regulation of E1A stability can be used to search for new effective drug combinations based on the adenoviral E1A protein.