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

被引:66
作者
Jol, H
Zhang, R
Zhang, H
McKinsey, TA
Shao, JY
Beauchamp, RD
Ballard, DW
Liang, P
机构
[1] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Howard Hughes Med Inst, Dept Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA
关键词
Ras; NF-kappa B; abnormal cell proliferation; growth inhibition;
D O I
10.1038/sj.onc.1203392
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:841 / 849
页数:9
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