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A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei.

The transcription factor nuclear factor-kappaB (NF-kappaB) plays crucial roles in a wide variety of cellular functions and its activity is strictly regulated by cytosolic inhibitors known as IkappaBs. We here report a new member of the IkappaB protein family, IkappaB-zeta, harboring six ankyrin repeats at its carboxyl terminus. IkappaB-zeta mRNA is strongly induced after stimulation by lipopolysaccharide. The induction of IkappaB-zeta is also observed by stimulation with interleukin-1beta but not by tumor necrosis factor-alpha. In contrast to cytosolic IkappaB-alpha, -beta, and -epsilon, the induced IkappaB-zeta localizes in the nucleus via its amino-terminal region, which shows no homology with other proteins. Transiently expressed IkappaB-zeta inhibits the NF-kappaB activity without affecting the nuclear translocation of NF-kappaB upon stimulation. The expressed IkappaB-zeta preferentially associates with the NF-kappaB subunit p50 rather than p65 and recombinant IkappaB-zeta proteins inhibit the DNA binding of the p65/p50 heterodimer and the p50/p50 homodimer. Thus, IkappaB-zeta negatively regulates NF-kappaB activity in the nucleus, possibly in order to prevent excessive inflammation. Moreover, transfection of IkappaB-zeta renders cells more susceptible to apoptosis induced by tumor necrosis factor-alpha. The proapoptotic activity of IkappaB-zeta further suggests that it might be one of key regulators for inflammation and other biologically relevant processes.

Pubmed ID: 11356851

Authors

  • Yamazaki S
  • Muta T
  • Takeshige K

Journal

The Journal of biological chemistry

Publication Data

July 20, 2001

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Nucleus
  • DNA Primers
  • I-kappa B Proteins
  • Lipopolysaccharides
  • Macrophages, Peritoneal
  • Mice
  • Molecular Sequence Data
  • NF-kappa B
  • Protein Isoforms
  • RNA, Messenger
  • Sequence Homology, Amino Acid