Sef Is an Inhibitor of Proinflammatory Cytokine Signaling, Acting by Cytoplasmic Sequestration of NF-κB
2012
Summary The
NF-κBtranscription factor controls diverse biological processes. According to the classical model,
NF-κBis retained in the cytoplasm of resting cells via binding to inhibitory, IκB proteins and translocates into the nucleus upon their ligand-induced degradation. Here we reveal that Sef, a known tumor suppressor and inhibitor of growth factor signaling, is a spatial regulator of
NF-κB. Sef expression is regulated by the
proinflammatory cytokinestumor necrosis factor and interleukin-1, and Sef specifically inhibits "classical"
NF-κB(
p50:p65) activation by these ligands. Like IκBs, Sef sequesters
NF-κBin the cytoplasm of resting cells. However, contrary to IκBs, Sef continues to constrain
NF-κBnuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown markedly enhances stimulus-induced
NF-κBnuclear translocation and consequent activity. This study establishes Sef as a feedback antagonist of
proinflammatory cytokinesand highlights its potential to regulate the crosstalk between
proinflammatory cytokinereceptors and
receptor tyrosine kinases.
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