Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.
Copyright policy )Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.
Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappaB). NF-kappaB is sequestered in the cytosol by Ikappa Balpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappaB in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and activated upon TNF exposure. Within the same time frame, TNF induced c-Src associates with Ikappa Balpha in a long lived complex. The proto-oncogene, when associated with Ikappa Balpha phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced Ikappa Balpha tyrosine phosphorylation, NF-kappaB activation, by the cytokine, is markedly delayed and reduced in c-src-/- BMMs. Underscoring the physiological significance of c-Src activation of NF-kappaB, TNF induction of IL-6, which is an NF-kappaB mediated event, is substantially diminished in c-src-/- BMMs.
- University of Mary United States
Male, Mice, Inbred C3H, Base Sequence, Interleukin-6, Tumor Necrosis Factor-alpha, Macrophages, Proto-Oncogene Proteins pp60(c-src), NF-kappa B, Bone Marrow Cells, DNA-Binding Proteins, Mice, NF-KappaB Inhibitor alpha, Animals, Tyrosine, I-kappa B Proteins, Phosphorylation, DNA Primers
Male, Mice, Inbred C3H, Base Sequence, Interleukin-6, Tumor Necrosis Factor-alpha, Macrophages, Proto-Oncogene Proteins pp60(c-src), NF-kappa B, Bone Marrow Cells, DNA-Binding Proteins, Mice, NF-KappaB Inhibitor alpha, Animals, Tyrosine, I-kappa B Proteins, Phosphorylation, DNA Primers
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