Oncoprotein suppression of tumor necrosis factor-induced NF kappa B activation is independent of Raf-controlled pathways.
Extensive data indicate that the transcription factor NF kappa B is activated by signals downstream of oncoproteins such as Ras or breakpoint cluster region (BCR)-ABL. Consistent with this, evidence has been presented that NF kappa B activity is required for Ras and BCR-ABL to transform cells. However, it remains unclear whether these oncoproteins activate a full spectrum of NF kappa B-dependent gene expression or whether they may augment or interfere with other stimuli that activate NF kappa B. The data presented here indicate that BCR-ABL expression in 32D myeloid cells or oncogenic Ras expression in murine fibroblasts blocks the ability of tumor necrosis factor (TNF) to activate NF kappa B. This suppression of NF kappa B is manifested by an inhibition of TNF-induced inhibitor of NF kappa B (IKK) activity and NF kappa B DNA binding potential but not by blocking TNF-induced nuclear accumulation of NF kappa B/p65. The inhibition of NF kappa B is not observed in oncogenic Raf-expressing cells and is not fully restored by the suppression of PI3-kinase or MEK pathways. Oncogenic Ras suppresses the ability of TNF to activate the expression of NF kappa B-dependent genes, such as iNOS (inducible nitric oxide synthase) and RANTES (regulated on activation normal T-cell expressed and secreted). These studies suggest that the ability of Ras and BCR-ABL to activate NF kappa B involves an uncharacterized pathway that does not involve classic IKK activity and that suppresses the TNF-induced IKK pathway through a Raf/MEK/Erk-independent mechanism.
Hanson
Julie L
JL
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, 27599-7295, USA.
Anest
Vasiliki
V
Reuther-Madrid
Julie
J
Baldwin
Albert S
AS
D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D017930:Genes, Reporter; D011905:Genes, ras; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D019908:Proto-Oncogene Proteins c-raf