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 differenti ation through the activation of Raf-dependent and Raf independent sign al transduction pathways and the subsequent activation of specific tra nscription factors, The transcription factor NF-kappa B has been widel y studied as a regulator of genes involved in immune and inflammatory responses, A variety of stimuli activate NF-kappa B through the induce d phosphorylation and degradation of the inhibitor I kappa B followed by nuclear translocation of NF-kappa B. We show here that oncogenic fo rms of Ha-Ras activate NF-kappa B, not through induced nuclear translo cation, but rather through the activation of the transcriptional funct ion of the NF-kappa B RelA/p65 subunit, Importantly, RelA/p65 -/- cell s are inefficient in the activation of kappa B-dependent gene expressi on in response to oncogenic Ras expression, Furthermore, I kappa B alp ha expression blocks focus formation in NIH3T3 cells induced by oncoge nic Ras, These results demonstrate that NF-kappa B is a critical downs tream mediator of Ha-Ras signaling and oncogenic potential.