Oncogenic mutations in I as lead to constitutive activation of downstream s
ignaling pathways that modulate the activities of transcription factors, In
turn, these factors control the expression of a subset of genes responsibl
e for neoplastic cell transformation. Recent studies suggest that transcrip
tion factor NF-kappa B contributes to cell transformation by inhibiting the
cell death signal activated by oncogenic Ras, In this study, inhibition of
NF-kappa B activity by forced expression of a super-repressor form of I ka
ppa-B alpha, the major inhibitor of NF-kappa B, markedly decreased the grow
th rate, saturation density and tumorigenicity of oncogenic H-Ras transform
ed rat embryo fibroblasts, Such clonally isolated cells overexpressing I ka
ppa B alpha super-repressor not only were viable but also exhibited no sign
of spontaneous apoptosis, Inhibition of NF-kappa B in these cells was func
tionally demonstrated by both the loss of cytokine induced DNA binding acti
vity and a profoundly increased sensitivity to cell death in response to TN
F-alpha treatment, In contrast, inhibition of NF-kappa B activity in non-tr
ansformed fibroblasts had minimal effect on growth, but rendered the cells
resistant to a subsequent transformation by H-ras oncogene, Similar results
were also obtained with rat intestinal epithelial cells harboring an induc
ible ras oncogene, Taken together, these findings suggest that NF-kappa B a
ctivity is essential for abnormal cell proliferation and tumorigenicity act
ivated by the ras oncogene and highlight an alternative functional role for
NF-kappa B in oncogenic Ras-mediated cell transformation that is distinct
from its anti-apoptotic activity.