Oncogenic Ha-Ras-induced signaling activates NF-kappa B transcriptional activity, which is required for cellular transformation

Ras proteins function in stimulating cell proliferation and differentiation through the activation of Raf-dependent and Raf independent signal transduction pathways and the subsequent activation of specific transcription factors, The transcription factor NF-kappa B has been widely studied as a regulator of genes involved in immune and inflammatory responses, A variety of stimuli activate NF-kappa B through the induced phosphorylation and degradation of the inhibitor I kappa B followed by nuclear translocation of NF-kappa B. We show here that oncogenic forms of Ha-Ras activate NF-kappa B, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-kappa B RelA/p65 subunit, Importantly, RelA/p65 -/- cells are inefficient in the activation of kappa B-dependent gene expression in response to oncogenic Ras expression, Furthermore, I kappa B alpha expression blocks focus formation in NIH3T3 cells induced by oncogenic Ras, These results demonstrate that NF-kappa B is a critical downstream mediator of Ha-Ras signaling and oncogenic potential.