Contributes to the regulation of transcriptional activation of NF-kappa-B target genes. In the cytoplasm, inhibits the nuclear translocation of the NF-kappa-B p50 subunit. In the nucleus, acts as transcriptional activator that promotes transcription of NF-kappa-B target genes. Contributes to the regulation of cell proliferation (By similarity).
Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly with p50B (NFKB2, p52) homodimers in cells, and together these proteins form a ternary complex with DNA at kappa B sites. Such an association functionally leads to a novel and potent form of transactivation through the kappa B motif: the tethering of Bcl-3 to DNA via the p50B homodimers allows Bcl-3 to transactivate directly, while p50B homodimers alone cannot. Transactivation mediated by Bcl-3 requires two cooperating domains located amino- and carboxy-terminal to the ankyrin domain. Bcl-3 is localized to the nucleus, and a Bcl-3-p50B complex is detected in certain lymphoid cells. Our data reveal a novel role for Bcl-3, distinct from that of the inhibitor I kappa B. The results have implications for tumorigenesis.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionUniProtKB
Bcl10 overexpression and nuclear translocation were originally identified in mucosa-associated lymphoid tissue lymphoma with t(1;14)(p32;q32) chromosome translocation. DNA amplification of Bcl10 was also found in other solid tumors. We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin. Oncol. 22, 3491-3497). However, the molecular mechanism of Bcl10 nuclear translocation remains unknown. In this study, we observed that tumor necrosis factor-alpha (TNFalpha) up-regulates the expression of Bcl10 and induces a fraction of Bcl10 nuclear translocation in human breast carcinoma MCF7 cells. Chromatin immunoprecipitation assays and electrophoretic mobility shift assays indicated that an NF-kappaB-binding site resides in the Bcl10 5 '-untranslated region. This study also demonstrates that Akt1, activated by TNFalpha, phosphorylates Bcl10 at Ser218 and Ser231 and that phosphorylated Bcl10 subsequently complexes with Bcl3 to enter the nucleus. Either inhibition of Akt1 or depletion of Bcl3 blocks Bcl10 nuclear translocation. In summary, these findings characterize a molecular linkage that directs Bcl10 nuclear translocation in response to TNFalpha treatment.
Evidence
2:
Inferred from Physical InteractionUniProtKB
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
Evidence
3:
Inferred from Physical InteractionUniProtKB
The proto-oncoprotein Bcl-3 is a member of the IkappaB family and is present predominantly in the nucleus. To gain insight into specific nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identified four novel binding partners of Bcl-3 in addition to NF-kappaB 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 PolII holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kappaB 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-kappaB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kappaB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kappaB 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.
Evidence
4:
Inferred from Physical InteractionIntAct
Proteome-scale protein interaction maps are available for many organisms, ranging from bacteria, yeast, worms and flies to humans. These maps provide substantial new insights into systems biology, disease research and drug discovery. However, only a small fraction of the total number of human protein-protein interactions has been identified. In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins. The data set has a validation rate of over 72% as determined by three independent biochemical or cellular assays. The network includes metabolic enzymes and liver-specific, liver-phenotype and liver-disease proteins that are individually critical for the maintenance of liver functions. The liver enriched proteins had significantly different topological properties and increased our understanding of the functional relationships among proteins in a liver-specific manner. Our data represent the first comprehensive description of a HLPN, which could be a valuable tool for understanding the functioning of the protein interaction network of the human liver.
The binding activity of a molecule that brings together two or more protein molecules, or a protein and another macromolecule or complex, through a selective, non-covalent, often stoichiometric interaction, permitting those molecules to function in a coordinated way.
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
Sequence-specific DNA binding transcription factor activitydefinition[GO:0003700]‹silver
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) express CD30 at high levels, but stimulation of this molecule has been reported to induce contradictory effects. To elucidate the molecular mechanism of CD30-mediated apoptosis of ALCL, we compared the gene expression profiles of t(2;5)(p23;q35)-positive ALCL with those of HL altered by CD30 agonistic stimulation. The results showed that BCL3, the high-level expression of which in ALCL was previously reported, was further upregulated in response to CD30 stimulation, along with several pro-apoptotic genes. Bcl-3 protein was present as an intermediate phospho-form in the resting-state ALCL, becoming hyperphosphorylated (Bcl-3P) upon stimulation. We next found that the stimulation promoted de novo synthesis of the nuclear factor (NF)-kappaB2/p100 precursor as well as processing to p52, and a series of immunoprecipitation and western blotting analyses consistently showed association of Bcl-3P with p52 in CD30-stimulated ALCL. An electrophoretic mobility shift assay revealed the induction of kappaB binding activity of the p52 homodimer, and nuclear colocalization of Bcl-3 and p52 was demonstrated in anaplastic lymphoma kinase-positive ALCL tumor tissues by immunohistochemistry. As Bcl-3 can act as an anti-repressor or transactivator or both, we propose that the (p52)2/Bcl-3P ternary complex, which is specifically induced in CD30-stimulated ALCL, can modulate expression of apoptosis-related genes regulated by NF-kappaB, thereby accounting for CD30-mediated apoptosis of ALCL.
Evidence
2:
Inferred from Physical InteractionUniProtKB
NF-kappa B is a transcription factor whose nuclear residence is controlled by I kappa B family members. In the NF-kappa B-I kappa B autoregulatory loop, activated (nuclear) Rel A.NF-kappa B1 induces the resynthesis of I kappa B alpha recapturing nuclear Rel A back into the cytoplasm within 1 h of stimulation. In contrast, NF-kappa B1 subunits redistribute more slowly into the cytoplasm (from 6 to 12 h). Here we examine the role of inducible cytoplasmic BCL-3 expression in terminating nuclear NF-kappa B1. Although BCL-3 is a nuclear protein in B lymphocytes, surprisingly, BCL-3 is primarily a cytoplasmic protein in HepG2 cells. Cytoplasmic BCL-3 abundance is induced 6-12 h after tumor necrosis factor-alpha stimulation where it complexes with NF-kappa B1 homodimers. Moreover, BCL-3 mRNA and protein expression are induced by NF-kappa B-activating agents. Two observations are interpreted to indicate that bcl-3 is transactivated by NF-kappa B/Rel A: 1) expression of a dominant negative NF-kappa B inhibitor blocks tumor necrosis factor-alpha-induced BCL-3 expression and 2) expression of constitutively active Rel A is sufficient to induce BCL-3 expression. In gene transfer studies, we identify two high affinity NF-kappa B-binding sites, kappa B1 (located at -872 to -861 nucleotides) and kappa B2 (-106 to -96 nucleotides), and although both bind with high affinity to Rel A, only kappa B2 is required for NF-kappa B-dependent induction of the native BCL-3 promoter. Down-regulation of BCL-3 induction results in prolonged, enhanced NF-kappa B1 binding and increased NF-kappa B-dependent transcription. Together, these data suggest the presence of an NF-kappa B-BCL-3 autoregulatory loop important in terminating NF-kappa B1 action and that individual NF-kappa B isoforms are actively terminated through coordinate induction of inhibitory I kappa B molecules to restore cellular homeostasis.
Evidence
3:
Inferred from Physical InteractionUniProtKB
BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.
Evidence
4:
Inferred from Physical InteractionUniProtKB
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
An immune response against microbes mediated through a body fluid. Examples of this process are seen in the antimicrobial humoral response of Drosophila melanogaster and Mus musculus.
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of an extracellular matrix.
The process in which germinal centers form. A germinal center is a specialized microenvironment formed when activated B cells enter lymphoid follicles. Germinal centers are the foci for B cell proliferation and somatic hypermutation.
IEAOrtholog Compara
Humoral immune response mediated by circulating immunoglobulindefinition[GO:0002455]‹silver
An immune response dependent upon secreted immunoglobulin. An example of this process is found in Mus musculus.
The process in which a signal is passed on to downstream components within the cell through the I-kappaB-kinase (IKK)-dependent activation of NF-kappaB. The cascade begins with activation of a trimeric IKK complex (consisting of catalytic kinase subunits IKKalpha and/or IKKbeta, and the regulatory scaffold protein NEMO) and ends with the regulation of transcription of target genes by NF-kappaB. In a resting state, NF-kappaB dimers are bound to I-kappaB proteins, sequestering NF-kappaB in the cytoplasm. Phosphorylation of I-kappaB targets I-kappaB for ubiquitination and proteasomal degradation, thus releasing the NF-kappaB dimers, which can translocate to the nucleus to bind DNA and regulate transcription.
BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediatordefinition[GO:0042771]
A series of molecular signals in which an intracellular signal is conveyed to trigger the apoptotic death of a cell. The pathway is induced by the cell cycle regulator phosphoprotein p53, or an equivalent protein, in response to the detection of DNA damage, and ends when the execution phase of apoptosis is triggered.
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
Any process in which a protein is maintained in the nucleus and prevented from moving elsewhere. These include sequestration within the nucleus, protein stabilization to prevent transport elsewhere and the active retrieval of proteins that escape the nucleus.
BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.
The process in which a B cell in the spleen acquires the specialized features of a marginal zone B cell. Marginal zone B cells are localized in a distinct anatomical region of the spleen that represents the major antigen-filtering and scavenging area (by specialized macrophages resident there). It appears that they are preselected to express a BCR repertoire similar to B-1 B cells, biased toward bacterial cell wall constituents and senescent self-components (such as oxidized LDL).
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of interleukin-8.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
Negative regulation of tumor necrosis factor biosynthetic processdefinition[GO:0042536]‹silver
Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of tumor necrosis factor, an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and which is responsible for a diverse range of signaling events within cells, leading to necrosis or apoptosis.
Any process that activates or increases the frequency, rate, or extent of interferon-gamma production. Interferon-gamma is also known as type II interferon.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of interleukin-10.
IEAOrtholog Compara
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944]‹silver
Any process that activates or increases the frequency, rate or extent of transcription from an RNA polymerase II promoter.
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of proteins by the translation of mRNA.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
A protein transport process that contributes to protein import into the nucleus, and that results in the vectorial transfer of a cargo-carrier protein complex through the nuclear pore complex from the cytoplasmic side to the nucleoplasmic side of the nuclear envelope.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
Bcl10 overexpression and nuclear translocation were originally identified in mucosa-associated lymphoid tissue lymphoma with t(1;14)(p32;q32) chromosome translocation. DNA amplification of Bcl10 was also found in other solid tumors. We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin. Oncol. 22, 3491-3497). However, the molecular mechanism of Bcl10 nuclear translocation remains unknown. In this study, we observed that tumor necrosis factor-alpha (TNFalpha) up-regulates the expression of Bcl10 and induces a fraction of Bcl10 nuclear translocation in human breast carcinoma MCF7 cells. Chromatin immunoprecipitation assays and electrophoretic mobility shift assays indicated that an NF-kappaB-binding site resides in the Bcl10 5 '-untranslated region. This study also demonstrates that Akt1, activated by TNFalpha, phosphorylates Bcl10 at Ser218 and Ser231 and that phosphorylated Bcl10 subsequently complexes with Bcl3 to enter the nucleus. Either inhibition of Akt1 or depletion of Bcl3 blocks Bcl10 nuclear translocation. In summary, these findings characterize a molecular linkage that directs Bcl10 nuclear translocation in response to TNFalpha treatment.
BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IkappaB family protein that is involved in transcriptional regulation of a number of NF-kappaB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-kappaB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.
Any process that modulates the frequency, rate or extent of DNA binding. DNA binding is any process in which a gene product interacts selectively with DNA (deoxyribonucleic acid).
Evidence
1:
Inferred from Expression PatternUniProtKB
J. Biol. Chem. 272, 33132-33139 (1997)[PubMed:9407099]
IkappaB proteins control the subcellular localization and DNA binding activity of NF-kappaB transcription factors. BCL3 is a nuclear IkappaB that can inhibit or enhance the binding of NF-kappaB p50 or p52 homodimers to consensus DNA-binding (kappaB) sequences or form a kappaB-binding complex with homodimers. To study BCL3 function, we have used gel shift analysis and tagged protein and tagged DNA coprecipitation analyses. Our results show that at intermediate ratios of BCL3 to p52 all observed phosphoforms of BCL3 are able to form a kappaB-binding complex with p52 homodimers. At low BCL3/p52 ratios, BCL3 increases the rate of p52 homodimer binding to kappaB sites in the presence of nonconsensus DNA and dissociates from the complex. At high BCL3/p52 ratios, BCL3 forms a higher order inhibitory complex with p52 homodimers. All of these effects depend on BCL3 phosphorylation and relative concentration. These results indicate that BCL3 phosphorylation may affect its regulation of NF-kappaB-dependent transcription in vivo.
Any process that modulates the frequency, rate or extent of the transfer of NF-kappaB, a transcription factor for eukaryotic RNA polymerase II promoters, from the cytoplasm into the nucleus, across the nuclear membrane.
Evidence
1:
Inferred from Expression PatternUniProtKB
BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating damage to its DNA from environmental insults or errors during metabolism.
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a UV-C radiation stimulus. UV-C radiation (UV-C light) spans the wavelengths 100 to 290 nm.
While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer. However, an oncogenic role for Bcl-3 has not been clearly identified. Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity. Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2. The results provide insight into a mechanism whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from a virus.
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
The process whose specific outcome is the progression of the spleen over time, from its formation to the mature structure. The spleen is a large vascular lymphatic organ composed of white and red pulp, involved both in hemopoietic and immune system functions.
An immune response which is associated with resistance to intracellular bacteria, fungi, and protozoa, and pathological conditions such as arthritis, and which is typically orchestrated by the production of particular cytokines by T-helper 1 cells, most notably interferon-gamma, IL-2, and lymphotoxin.
The process in which a relatively unspecialized T cell acquires specialized features of a T-helper 2 (Th2) cell. A Th2 cell is a CD4-positive, alpha-beta T cell that has the phenotype GATA-3-positive and produces interleukin-4.
Respiratory syncytial virus (RSV) is a paramyxovirus that produces airway inflammation, in part by inducing interleukin-8 (IL-8) expression, a CXC-type chemokine, via the NF-kappaB/RelA and STAT/IRF signaling pathways. In RSV-infected A549 cells, IL-8 transcription attenuates after 24 h in spite of ongoing viral replication and persistence of nuclear RelA, suggesting a mechanism for transcriptional attenuation. RSV infection induces B-cell lymphoma protein -3 (Bcl-3) expression 6 to 12 h after viral infection, at times when IL-8 transcription is inhibited. By contrast, 293 cells, deficient in inducible Bcl-3 expression, show no attenuation of IL-8 transcription. We therefore examined Bcl-3's role in terminating virus-inducible IL-8 transcription. Transient expression of Bcl-3 potently inhibited virus-inducible IL-8 transcription by disrupting both the NF-kappaB and STAT/IRF pathways. Although previously Bcl-3 was thought to capture 50-kDa NF-kappaB1 isoforms in the cytoplasm, immunoprecipitation (IP) and electrophoretic mobility shift assays indicate that nuclear Bcl-3 associates with NF-kappaB1 without affecting DNA binding. Additionally, Bcl-3 potently inhibited the STAT/IRF pathway. Nondenaturing co-IP assays indicate that nuclear Bcl-3 associates with STAT-1 and histone deacetylase 1 (HDAC-1), increasing HDAC-1 recruitment to the IL-8 promoter. Treatment with the HDAC inhibitor trichostatin A blocks attenuation of IL-8 transcription. A nuclear targeting-deficient Bcl-3 is unable to enhance HDAC-1-mediated chemokine repression. Finally, small inhibitory RNA-mediated Bcl-3 "knockdown" resulted in enhanced RSV-induced chemokine expression in A549 cells. These data indicate that Bcl-3 is a virus-inducible inhibitor of chemokine transcription by interfering with the NF-kappaB and STAT/IRF signaling pathways by complexing with them and recruiting HDAC-1 to attenuate target promoter activity.
Protein involved in the transfer of genetic information from DNA to messenger RNA (mRNA) by DNA-directed RNA polymerase. In the case of some RNA viruses, protein involved in the transfer of genetic information from RNA to messenger RNA (mRNA) by RNA-directed RNA polymerase.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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