The NF-κB transcription factor controls diverse biological processes. According 
to the classical model, NF-κB is 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 cytokines tumor necrosis factor 
and interleukin-1, and Sef specifically inhibits "classical" NF-κB (p50:p65) 
activation by these ligands. Like IκBs, Sef sequesters NF-κB in the cytoplasm of 
resting cells. However, contrary to IκBs, Sef continues to constrain NF-κB 
nuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown 
markedly enhances stimulus-induced NF-κB nuclear translocation and consequent 
activity. This study establishes Sef as a feedback antagonist of proinflammatory 
cytokines and highlights its potential to regulate the crosstalk between 
proinflammatory cytokine receptors and receptor tyrosine kinases.