TY - JOUR
T1 - Sef Is an Inhibitor of Proinflammatory Cytokine Signaling, Acting by Cytoplasmic Sequestration of NF-κB
AU - Fuchs, Yaron
AU - Brunwasser, Michal
AU - Haif, Sasha
AU - Haddad, Jumana
AU - Shneyer, Boris
AU - Goldshmidt-Tran, Orit
AU - Korsensky, Lina
AU - Abed, Mona
AU - Zisman-Rozen, Simona
AU - Koren, Lilach
AU - Carmi, Yaron
AU - Apte, Ron
AU - Yang, Ruey Bing
AU - Orian, Amir
AU - Bejar, Jacob
AU - Ron, Dina
N1 - Funding Information:
We thank Stuart A. Aaronson, Amer Beg, Yinon Ben-Neriah, Aaron Ciechanover, Sankar Ghosh, Kazuhiro Iwai, Michael Karin, George Stark, and Beat Trueb for kindly providing reagents. We thank Dan Cassel, Amnon Harel, Philippa Melamed, Yinon Ben-Neriah, Igor Dawid, Ricardo Almuly, and Samara Brown for useful suggestions and Maayan Duvshani-Eshet and Edith Suss-Toby for assisting with the confocal microscopy. This work was supported by grants from the Israel Ministry of Health (#4113) and the Israel Cancer Association (#20092033) to D.R.
PY - 2012/9/11
Y1 - 2012/9/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866029214&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2012.07.013
DO - 10.1016/j.devcel.2012.07.013
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AN - SCOPUS:84866029214
SN - 1534-5807
VL - 23
SP - 611
EP - 623
JO - Developmental Cell
JF - Developmental Cell
IS - 3
ER -
