Abrogation of B-Raf(V600E) induced senescence by FoxM1 expression

Abstract

B-Raf(V600E) oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-Raf(V600E) in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-Raf(V600E) requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-Raf(V600E) and AKT signaling. B-Raf(V600E) activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by PTEN downregulation induced FoxM1 expression, and co-expression of B-Raf(V600E) and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-Raf(V600E)-induced senescence.