title: NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis.
abstract: 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.
authors.affiliation: The Vanderbilt-Ingram Cancer Center, Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jo
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: T A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: R D
authors.initials: RD
authors.lastname: Beauchamp
authors.forename: D W
authors.initials: DW
authors.lastname: Ballard
authors.forename: P
authors.initials: P
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats
chemical_list: D016328:NF-kappa B