A novel member of the IkappaB family, human IkappaB-zeta, inhibits transactivation of p65 and its DNA binding.
A novel member of the IkappaB family, human IkappaB-zeta, was identified by a differential screening approach of apoptosis-sensitive and -resistant tumor cells. The protein consists of 6 ankyrin repeats at its COOH terminus and shares about 30% identity with other IkappaB members. IkappaB-zeta associates with both the p65 and p50 subunit of NF-kappaB and inhibits the transcriptional activity as well as the DNA binding of the transcription factor. Interestingly, IkappaB-zeta is localized in the nucleus where it aggregates in matrix-associated deacetylase bodies, indicating that IkappaB-zeta regulates nuclear NF-kappaB activity rather than its nuclear translocation from the cytoplasm. IkappaB-zeta expression itself was regulated by NF-kappaB, suggesting that its activity is controlled in a negative feedback loop. Unlike classical IkappaB proteins, IkappaB-zeta was not degraded upon cell stimulation. Treatment with tumor necrosis factor-alpha, interleukin-1beta, and lipopolysaccharide induced a strong induction of IkappaB-zeta transcripts. Expression of IkappaB-zeta was detected in different tissues including lung, liver, and in leukocytes but not in the brain. Suppression of endogenous IkappaB-zeta by RNA interference rendered cells more resistant to apoptosis, whereas overexpression of IkappaB-zeta was sufficient to induce cell death. Our results, therefore, suggest that IkappaB-zeta functions as an additional regulator of NF-kappaB activity and, hence, provides another control level for the activation of NF-kappaB-dependent target genes.
Totzke
Gudrun
G
Institute of Molecular Medicine, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
Essmann
Frank
F
Pohlmann
Stephan
S
Lindenblatt
Charlotte
C
Jänicke
Reiner U
RU
Schulze-Osthoff
Klaus
K
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000502:physiology; D050863:Synaptotagmin I / Q000737:chemistry*; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D007375:Interleukin-1; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D050863:Synaptotagmin I; D014409:Tumor Necrosis Factor-alpha; D004247:DNA