The NF-κB/Rel and IκB gene families: mediators of immune response and inflammation

Wulczyn, F. Gregory; Krappmann, Daniel; Scheidereit, Claus

doi:10.1007/s001090050078

Cited by 243 publications

(160 citation statements)

References 193 publications

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“…Bcl-3 can associate with p50 and depending on the conditions the Bcl-3 complex dissociates from DNA or stays bound, resulting in the formation of a ternary complex (Wulczyn et al, 1996). To examine the consequences of the novel Bcl-3 interactions on p50/ Bcl-3 complexes we choose experimental conditions where p50 and Bcl-3 are bound to each other and to DNA ( Figure 2).…”

Section: Bcl-3 Interacts With Several Nuclear Co-factorsmentioning

confidence: 99%

“…Bcl-3 is a member of the IkB multigene family which modulates the activities of NF-kB/Rel transcription factors (Baeuerle and Baltimore, 1996;Baldwin, 1996;Siebenlist, 1997;Wulczyn et al, 1996). The mammalian NF-kB/Rel family consists of ®ve proteins to date: p50, p52, RelA (p65), c-Rel and RelB; p50 and p52 are generated by processing from their precursors, p105 and p100, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Dimers of NF-kB/Rel factors are sequestered into the cytoplasm by the IkB proteins IkBa, IkBb and IkBe. In addition, the precursor proteins p100 and p105 have IkB properties and can withdraw NF-kB/Rel factors into cytoplasmic complexes (Wulczyn et al, 1996). A common feature of all IkB family members, including Bcl-3, is a domain of six to seven ankyrin repeats which serves as a protein interaction surface and binds to the conserved Relhomology domain of NF-kB/Rel dimers.…”

Section: Introductionmentioning

confidence: 99%

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The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators

et al. 1999

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The proto-oncoprotein Bcl-3 is a member of the IkB family and is present predominantly in the nucleus. To gain insight into speci®c nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identi®ed four novel binding partners of Bcl-3 in addition to NF-kB p50 and p52, previously known to associate with Bcl-3. The novel Bcl-3 interactors Jab1, Pirin, Tip60 and Bard1 are nuclear proteins which also bind to other transcription factors including c-Jun, nuclear factor I (NFI), HIV-1 Tat or the tumor suppressor and Polll holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kB DNA binding sites, whereas Jab1 enhances p50-Bcl-3-DNA complex formation. Furthermore, the histone acetylase Tip60 enhances Bcl-3-p50 activated transcription through an NF-kB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kB p50/p52 and other transcription regulators and suggest that its gene activation function may at least in part be due to recruitment of the Tip60 histone actetylase.

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Section: Bcl-3 Interacts With Several Nuclear Co-factorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators

et al. 1999

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“…NF-kB/Rel transcription factors mediate the expression of numerous genes involved in diverse functions such as in¯ammation, immune response, apoptosis and cell proliferation (Siebenlist et al, 1994;Wulczyn et al, 1996;May and Ghosh, 1997;Sonenshein, 1997;Luque and Gelinas, 1997). The mammalian NF-kB/Rel family comprises ®ve members (p50, p52, p65(RelA), c-Rel and RelB) which form various homo-and heterodimers and are tightly regulated by a group of IkB proteins (IkBa,IkBb,IkBe,p105,.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells

et al. 1999

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A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-kB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-kB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive IkBa, no signi®cant changes in NF-kB or IkB expression were seen in other H-RS cells (L591, L1236 and HDLM-2). Constitutive NF-kB was susceptible to inhibition by recombinant IkBa, suggesting that neither mutations in the NF-kB genes nor posttranslational modi®cations of NF-kB were involved. Endogenous IkBa was bound to p65 and displayed a very short half-life. IkBa degradation could be blocked by inhibitors of the NF-kB activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated IkBa and a reduction of NF-kB activity in HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitutive IkB kinase (IKK) activity in H-RS cells, indicating ongoing signal transduction. Furthermore, H-RS cells secrete one or more factor(s) that were able to trigger NF-kB activation. We conclude that aberrant activation of IKK's, and in some cases defective IkBs, lead to constitutive nuclear NF-kB activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.

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“…The deficiency stems from impaired nuclear localization of the RelA/p50 heterodimer, a problem that has been noted in both tumor-infiltrating lymphocytes (TIL) 3 and peripheral blood T cells isolated from patients with renal cell carcinoma (RCC) (15)(16)(17). Coincident with impaired NF-B is the demonstrated enhanced susceptibility of RCC patient T cells, particularly TILs, to apoptosis (18).…”

mentioning

confidence: 99%

Degradation of NF-κB in T Cells by Gangliosides Expressed on Renal Cell Carcinomas

Thornton¹,

Kudo

Rayman³

et al. 2004

The Journal of Immunology

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T cells from cancer patients are often functionally impaired, which imposes a barrier to effective immunotherapy. Most pronounced are the alterations characterizing tumor-infiltrating T cells, which in renal cell carcinomas includes defective NF-κB activation and a heightened sensitivity to apoptosis. Coculture experiments revealed that renal tumor cell lines induced a time-dependent decrease in RelA(p65) and p50 protein levels within both Jurkat T cells and peripheral blood T lymphocytes that coincided with the onset of apoptosis. The degradation of RelA/p50 is critical for SK-RC-45-induced apoptosis because overexpression of RelA in Jurkat cells protects against cell death. The loss of RelA/p50 coincided with a decrease in expression of the NF-κB regulated antiapoptotic protein Bcl-xL at both the protein and mRNA level. The disappearance of RelA/p50 protein was mediated by a caspase-dependent pathway because pretreatment of T lymphocytes with a pan caspase inhibitor before coculture with SK-RC-45 blocked RelA and p50 degradation. SK-RC-45 gangliosides appear to mediate this degradative pathway, as blocking ganglioside synthesis in SK-RC-45 cells with the glucosylceramide synthase inhibitor, PPPP, protected T cells from tumor cell-induced RelA degradation and apoptosis. The ability of the Bcl-2 transgene to protect Jurkat cells from RelA degradation, caspase activation, and apoptosis implicates the mitochondria in these SK-RC-45 ganglioside-mediated effects.

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The NF-κB/Rel and IκB gene families: mediators of immune response and inflammation

Cited by 243 publications

References 193 publications

The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators

The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators

Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells

Degradation of NF-κB in T Cells by Gangliosides Expressed on Renal Cell Carcinomas

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