NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis.

Jo H, Zhang R, Zhang H, McKinsey TA, Shao J, Beauchamp RD, Ballard DW, Liang P
Oncogene. 2000 19 (7): 841-9

PMID: 10702792 · DOI:10.1038/sj.onc.1203392

Oncogenic mutations in ras 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. Oncogene (2000) 19, 841 - 849.

MeSH Terms (15)

Animals Apoptosis Cell Division Cell Line, Transformed Cell Survival Cell Transformation, Neoplastic Fibroblasts Genes, ras Humans Intestinal Mucosa Male Mice Mice, Nude NF-kappa B Rats

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