Jornal de Carcinogênese e Mutagênese

Abstrato

Downstream Signaling of the Sos Gene is Not Required during the Pathogenesis of Cancer Cells Bearing KRAS and BRAF Mutations

Tamimi Yahya, Al Busaidi Aisha, Gupta Ishita and AL Moundhri Mansour

The Braf/Ras-MAPK is a relevant signal transduction pathway involved in several processes of the cell cycle through activation by interacting with several growth factors and commonly mutated in several cancers. The Sos-1 and Sos-2 (Son of sevenless homolog-1/2) guanine nucleotide exchange factors play a key role in regulating the Ras protein to enable downstream pathway activation. In this study, we investigated the effect of Sos1 proteins on the regulation of the MAPK pathway in the presence and absence of KRAS and BRAF mutations, by monitoring the expression of the downstream proteins, MEK and ERK and their related phosphorylation forms. Our results revealed that knockdown of the Sos1 protein in cells harboring (G13D) and (G464V) mutations within KRAS and BRAF genes respectively did not affect the activation of the MAPK pathway. In contrast, cells with wild-type KRAS and BRAF exhibited decreased activation of MEK and ERK in response to Sos1 knockdown. This study suggests that MAPK pathway activation maneuvers independently of the upstream signaling from Sos1 when KRAS and BRAF mutations are present in tumor cells. Transduction of downstream signaling is likely due to mutations self-activation (gain-offunction mutations) or to the involvement of new oncoprotein involved in the onset of tumorogenesis through different pathway. Interaction of the different key players in this pathway tends to differ and can be critical for paving the pathway towards drug design and better therapy.