Sef Is an Inhibitor of Proinflammatory Cytokine Signaling, Acting by Cytoplasmic Sequestration of NF-κB
| Autor: | Ron N. Apte, Amir Orian, Lina Korsensky, Jumana Haddad, Yaron Fuchs, Dina Ron, Simona Zisman-Rozen, Michal Brunwasser, Ruey-Bing Yang, Yaron Carmi, Lilach Koren, Sasha Haif, Jacob Bejar, Boris Shneyer, Orit Goldshmidt-Tran, Mona Abed |
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| Rok vydání: | 2012 |
| Předmět: |
Cytoplasm
medicine.medical_treatment Biology General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Proinflammatory cytokine Mice chemistry.chemical_compound medicine Animals Humans Receptor Molecular Biology Transcription factor Cells Cultured Inflammation Growth factor NF-kappa B NF-κB Receptors Interleukin Cell Biology Cell biology HEK293 Cells Biochemistry chemistry NIH 3T3 Cells biology.protein Cytokines Tumor necrosis factor alpha Signal transduction HeLa Cells Signal Transduction Developmental Biology |
| Zdroj: | Developmental Cell. 23:611-623 |
| ISSN: | 1534-5807 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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