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

Citation
H. Jol et al., NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis, ONCOGENE, 19(7), 2000, pp. 841-849
Citations number
46
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
19
Issue
7
Year of publication
2000
Pages
841 - 849
Database
ISI
SICI code
0950-9232(20000217)19:7<841:NBIRFH>2.0.ZU;2-Z
Abstract
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.