Journal
FEBS JOURNAL
Volume 276, Issue 5, Pages 1459-1470Publisher
WILEY
DOI: 10.1111/j.1742-4658.2009.06888.x
Keywords
I kappa B alpha; nuclear factor-kappa B; nuclear translocation; Nucling; tumor necrosis factor-alpha
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Funding
- Ministry of Education, Science, Sports and Culture of Japan for the Promotion of Science
- Ministry of Health, Labor and Welfare of Japan
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Nucling is an Apaf1-binding proapoptotic protein involved in apoptosome-mediated apoptosis. Luciferase assays have revealed that the activation of nuclear factor-kappa B induced by tumor necrosis factor-alpha, interleukin-1 beta and lipopolysaccharide is downregulated by the overexpression of Nucling in HEK293 cells. Moreover, the expression of endogenous cyclooxygenase 2, tumor necrosis factor-alpha and galectin-3, the end-point molecules in the pathway for the activation of nuclear factor-kappa B, as well as nuclear factor-kappa B (p65) itself, is upregulated in Nucling gene-deficient mouse embryonic fibroblasts, suggesting that nuclear factor-kappa B is a target of Nucling. Subsequent study has revealed that Nucling physically interacts with nuclear factor-kappa B (p65 and p50) and that the binding domain of Nucling is its amino-terminal region (amino acids 1-466) containing ankyrin repeats. Overexpression of Nucling prevents the translocation of nuclear factor-kappa B into the nucleus. In addition, the cytoplasmic retention of endogenous nuclear factor-kappa B in resting cells is not observed in Nucling gene-deficient mouse embryonic fibroblasts. These results reveal a novel function of Nucling as a suppressor of nuclear factor-kappa B, mediated by its cytoplasmic retention through physical interaction.
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