期刊
ONCOGENE
卷 19, 期 7, 页码 841-849出版社
STOCKTON PRESS
DOI: 10.1038/sj.onc.1203392
关键词
Ras; NF-kappa B; abnormal cell proliferation; growth inhibition
资金
- NCI NIH HHS [CA74067, CA76960] Funding Source: Medline
- NIAID NIH HHS [AI33839] Funding Source: Medline
Oncogenic mutations in I as lead to constitutive activation of downstream signaling pathways that modulate the activities of transcription factors, In turn, these factors control the expression of a subset of genes responsible for neoplastic cell transformation. Recent studies suggest that transcription 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 kappa-B alpha, the major inhibitor of NF-kappa B, markedly decreased the growth rate, saturation density and tumorigenicity of oncogenic H-Ras transformed rat embryo fibroblasts, Such clonally isolated cells overexpressing I kappa 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 functionally demonstrated by both the loss of cytokine induced DNA binding activity and a profoundly increased sensitivity to cell death in response to TNF-alpha treatment, In contrast, inhibition of NF-kappa B activity in non-transformed 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 inducible ras oncogene, Taken together, these findings suggest that NF-kappa B activity is essential for abnormal cell proliferation and tumorigenicity activated 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.
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