Cloning and functional characterization of mouse IκBɛ

Simeonidis, Simos; Liang, Stanley; Chen, Guoying; Thanos, Dimitris

doi:10.1073/pnas.94.26.14372

Cited by 82 publications

(90 citation statements)

References 37 publications

(78 reference statements)

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“…IB-␣ was a much stronger NF-B inhibitor, indicating that the transcriptional activity of NF-B is regulated differentially by these two IB proteins. Such a weaker inhibition of NF-B activity in comparison to IB-␣ has been also reported for IB-⑀ (34).…”

Section: Nf-b Promoter Activity Is Inhibited By the Cooh-terminal Dommentioning

confidence: 81%

“…IB-␣ and IB-␤ interact with p65/p50 and c-Rel/p50 heterodimers, IB-⑀ associates only with homo-or heterodimeric complexes containing p65 and c-Rel (14,15,34), and Bcl-3 interacts specifically with p50 and p52 homodimers (22). In contrast, p100 and p105, which are precursors of the Rel proteins p52 and p50, respectively, appear to bind efficiently to all Rel proteins.…”

Section: Discussionmentioning

confidence: 94%

“…In addition, a higher amount of IB-was necessary to inhibit the binding of NF-B to the DNA, possibly due to a higher affinity of p65/p50 to IB-␣. A considerable weaker inhibition of NF-B DNA binding compared with IB-␣ has been reported for IB-⑀ (34).…”

Section: Discussionmentioning

confidence: 99%

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A Novel Member of the IκB Family, Human IκB-ζ, Inhibits Transactivation of p65 and Its DNA Binding

Totzke

Eßmann

Pohlmann

et al. 2006

Journal of Biological Chemistry

105

121

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A novel member of the IB family, human IB-, 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 IB members. IB-associates with both the p65 and p50 subunit of NF-B and inhibits the transcriptional activity as well as the DNA binding of the transcription factor. Interestingly, IB-is localized in the nucleus where it aggregates in matrix-associated deacetylase bodies, indicating that IB-regulates nuclear NF-B activity rather than its nuclear translocation from the cytoplasm. IBexpression itself was regulated by NF-B, suggesting that its activity is controlled in a negative feedback loop. Unlike classical IB proteins, IB-was not degraded upon cell stimulation. Treatment with tumor necrosis factor-␣, interleukin-1␤, and lipopolysaccharide induced a strong induction of IB-transcripts. Expression of IB-was detected in different tissues including lung, liver, and in leukocytes but not in the brain. Suppression of endogenous IB-by RNA interference rendered cells more resistant to apoptosis, whereas overexpression of IB-was sufficient to induce cell death. Our results, therefore, suggest that IB-functions as an additional regulator of NF-B activity and, hence, provides another control level for the activation of NF-B-dependent target genes.NF-B is an evolutionarily conserved pleiotropic transcription factor that plays a crucial role in many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis, and apoptosis (Refs. 2-6; for review, see Ref. 1). The mammalian NF-B/Rel family consists of RelA (p65), RelB, c-Rel, p50, and p52 that bind as homo-or heterodimers at B sites in the DNA of their target genes. This combinatorial diversity contributes to the regulation of a distinct but overlapping set of genes, in that the individual dimers have distinct preferences for different B sites that they can bind with distinguishable affinity and specificity. In addition, whether the transcription of a target gene is activated or repressed depends on the dimer combination. While RelA/ p50, RelA/c-Rel, RelB/p50, and RelB/p52 heterodimers are transcriptional activators, p50/p50 and p52/p52 homodimers generally repress transcription (7-9). Regulation of the great diversity of genes requires a precise control of NF-B, which is achieved by various mechanisms of posttranslational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. Dysregulation of NF-B activation results in a wide range of human disorders including inflammatory and neurodegenerative diseases (10, 11) and different types of cancer (4, 12).NF-B activity is also tightly regulated by interaction with IB proteins (13). Characteristic for all IB proteins is a domain of multiple ankyrin repeats that bind to the conserved Rel homology domain of NF-B proteins. Various members of the IB family target different NF-B complexes, e.g....

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Section: Nf-b Promoter Activity Is Inhibited By the Cooh-terminal Dommentioning

confidence: 81%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

A Novel Member of the IκB Family, Human IκB-ζ, Inhibits Transactivation of p65 and Its DNA Binding

Totzke

Eßmann

Pohlmann

et al. 2006

Journal of Biological Chemistry

105

121

View full text Add to dashboard Cite

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“…The recently cloned IB⑀ (60,62,63) has been reported to selectively interact with RelA homodimers, and both IB␣ and IB␤ are known to interact with RelA-containing heterodimers. The sequestration of various IBs through interaction with inappropriately regulated RelA protein might lead to nuclear translocation and target gene activation.…”

Section: Both the Dna Binding And Transactivation Domains Of Rela Arementioning

confidence: 99%

Overexpression of RelA Causes G1 Arrest and Apoptosis in a Pro-B Cell Line

Sheehy¹,

Schlissel

1999

Journal of Biological Chemistry

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Classical NF-B 1 is a heterodimer composed of two protein subunits, p50 and p65, that are members of the Rel family of transcription factors (1). This family consists of five known members, c-Rel, RelA (p65), RelB, p50, and p52 (2-6), and is identified by a characteristic N-terminal 300 amino acid Rel homology domain. This region contains sequences for DNA binding, dimerization, and nuclear localization. Association of Rel family dimers with a second family of proteins, the IBs, is responsible for the cytoplasmic sequestration of inactive NF-B in unstimulated cells (7).NF-B was originally identified as a B cell-specific transcription factor that bound to a decameric sequence within the intronic enhancer of the immunoglobulin (Ig) light chain gene (8). It had been shown previously that the B site within this enhancer is critical for enhancer activity in reporter assays (9) and that NF-B activation controlled the ability of this enhancer to activate transcription (10 -12). During early B cell development, Ig loci undergoing gene rearrangement were also transcriptionally active (13-15), and this activation correlated with the presence of active nuclear NF-B (8, 10). These observations led to the hypothesis that NF-B played a critical role in the activation of Ig locus transcription and rearrangement during early B cell development (9 -11, 14, 16). It was later appreciated that NF-B was in fact a ubiquitously expressed, inducible factor (17), responsible for the activation of a diverse array of genes (1), but its role in B cell development continues to be of significant interest.The role of NF-B in the developmental regulation of gene expression has been studied by generating mice deficient in individual Rel family members (18 -23). Whereas none of the single knock-out mice showed any obvious defect in early B cell development, a recent report of mice deficient in both p50 and p52 revealed an essential role for NF-B in the generation of mature B cells (24). Interestingly, mice deficient in either p50 or c-Rel have normal numbers of mature B cells, but these cells fail to activate appropriately in response to antigen receptor stimulation leading to humoral immunodeficiency (18,20). The role of RelA in B cell development could not be assessed since deficiency in this factor proved lethal by day 15 of embryogenesis, although adoptive transfer experiments suggested that B cell expression of RelA was not required for normal development (21, 25). Evaluation of RelA-deficient pre-morbid fetuses attributed death to massive liver cell apoptosis. Thus, whereas their precise role in early B cell development remains uncertain, genetic studies implicate Rel family members in the regulation of both cell activation and cell death.A variety of other studies has demonstrated a role for NF-B in both protection from and induction of apoptosis (26 -32). These reports encompass a range of both cell types and apoptosis-inducing stimuli. Additional observations have suggested a role for NF-B in growth arrest and differentiation (24,25,(33...

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“…Depending on the cell type and stimulus, IkBs respond di erentially to various inducers of NF-kB. IkBa is a stronger inhibitor of nuclear NF-kB activity than IkBb or IkBe (Simeonidis et al, 1997;Tran et al, 1997). In human endothelial cells, TNF caused sustained reduction in the levels of IkBb, resulting in persistent activation of NF-kB and induction of NF-kB-regulated genes (Johnson et al, 1996).…”

Section: Discussionmentioning

confidence: 99%