TY - JOUR
T1 - Tumor necrosis factor-α activation of nuclear transcription factor-κB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of IκBα
AU - Abu-Amer, Yousef
AU - Rossl, F. Patrick
AU - McHugh, Kevin P.
AU - Livolsi, Antonia
AU - Peyron, Jean Francois
AU - Teitelbaum, Steven L.
PY - 1998/11/6
Y1 - 1998/11/6
N2 - Tumor necrosis factor-α (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-κ B (NF-κB). NF-κB is sequestered in the cytosol by IκBα 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- κB 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 IκBα in a long lived complex. The proto-oncogene, when associated with IκBα phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced IκBα tyrosine phosphorylation, NF-κB activation, by the cytokine, is markedly delayed and reduced in c-src-/BMMs. Underscoring the physiological significance of c-Src activation of NF-κB, TNF induction of IL-6, which is an NF-κB mediated event, is substantially diminished in c- src-/- BMMs.
AB - Tumor necrosis factor-α (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-κ B (NF-κB). NF-κB is sequestered in the cytosol by IκBα 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- κB 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 IκBα in a long lived complex. The proto-oncogene, when associated with IκBα phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced IκBα tyrosine phosphorylation, NF-κB activation, by the cytokine, is markedly delayed and reduced in c-src-/BMMs. Underscoring the physiological significance of c-Src activation of NF-κB, TNF induction of IL-6, which is an NF-κB mediated event, is substantially diminished in c- src-/- BMMs.
UR - http://www.scopus.com/inward/record.url?scp=0032491410&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.45.29417
DO - 10.1074/jbc.273.45.29417
M3 - Article
C2 - 9792645
AN - SCOPUS:0032491410
VL - 273
SP - 29417
EP - 29423
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 45
ER -