Regulation of NFKB1 proteins by the candidate oncoprotein BCL-3: generation of NF-kappa B homodimers from the cytoplasmic pool of p50-p105 and nuclear translocation

Watanabe, Nobumasa; Iwamura, Tomokatsu; Shinoda, Tomoyasu; Fujita, Takashi

doi:10.1093/emboj/16.12.3609

Cited by 105 publications

(110 citation statements)

References 54 publications

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“…Consistent with this concept, the phenotype of the Bcl-3 knockout overlaps signi®cantly with that of the p50 and the p52 knockouts (Caamano et al, 1998;Franzozo et al, 1997Franzozo et al, , 1998Schwarz et al, 1997). Importantly, we ®nd that Bcl-3 nuclear levels are increased in breast cancer tissue as compared to the adjacent levels, which is interesting since it was published recently that Bcl-3 can function to increase nuclear levels of p50 (Zhang et al, 1994;Watanabe et al, 1997). Thus, an increase in nuclear Bcl-3 may function with increased levels of p50 and p52 to account for the enhancement in NF-kB dependent gene expression observed in human breast cancer ( Figure 5).…”

Section: Discussionsupporting

confidence: 56%

“…IkBb also interacts with the same heterodimers as IkBa but is degraded with slower kinetics and functions in the persistent activation of NF-kB (Ghosh et al, 1998). Bcl-3, a noninhibitory member of the IkB family (Ohno et al, 1990;Kerr et al, 1992) that is associated with certain leukemias and lymphomas (McKeithan et al, 1997), functions to stimulate transcription through interactions with the p50 or p52 NF-kB subunits (Bours et al, 1993;Fujita et al, 1993) and to increase nuclear levels of p50 homodimers (Zhang et al, 1994;Watanabe et al, 1997). Bcl-3-p50 complexes can be activated following inducible phosphorylation of the p105 precursor by the IkB kinase .…”

Section: Introductionmentioning

confidence: 99%

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Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3

et al. 2000

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Members of the NF-kB/Rel transcription factor family have been shown recently to be required for cellular transformation by oncogenic Ras and by other oncoproteins and to suppress transformation-associated apoptosis. Furthermore, NF-kB has been shown to be activated by several oncoproteins including HER2/Neu, a receptor tyrosine kinase often expressed in human breast cancer. Human breast cancer cell lines, human breast tumors and normal adjacent tissue were analysed by gel mobility shift assay, immunoblotting of nuclear extracts and immunohistochemistry for activation of NF-kB. Furthermore, RNA levels for NF-kB-activated genes were analysed in order to determine if NF-kB is functionally active in human breast cancer. Our data indicate that the p65/RelA subunit of NF-kB is activated (i.e., nuclear) in breast cancer cell lines. However, breast tumors exhibit an absence or low level of nuclear p65/RelA but show activated c-Rel, p50 and p52 as compared to nontumorigenic adjacent tissue. Additionally, the IkB homolog Bcl-3, which functions to stimulate transcription with p50 or p52, was also activated in breast tumors. There was no apparent correlation between estrogen receptor status and levels of nuclear NF-kB complexes. Transcripts of NF-kB-regulated genes were found elevated in breast tumors, as compared to adjacent normal tissue, indicating functional NF-kB activity. These data suggest a potential role for a subset of NF-kB and IkB family proteins, particularly NF-kB/p52 and Bcl-3, in human breast cancer. Additionally, the activation of functional NF-kB in these tumors likely involves a signal transduction pathway distinct from that utilized by cytokines.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3

et al. 2000

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“…30 Bcl-3 protein levels are high in such leukemias, as well as in some lymphomas, including a subgroup of anaplastic large lymphoma (ACLC) with t(2;5)(q23;q35), where a combination of genetic and epigenetic modifications is supposed to lead to bcl-3 overexpression. [31][32] Bcl-3 protein shares with IkB family proteins the presence of ankyrin domains; however, at variance with the other IkB proteins, it is mainly nucleoplasmic and can enhance NFkB-dependent transcription (33)(34)(35). Indeed, in the cell nucleus, Bcl-3 can either interact with suppressor p50 homodimers and remove them from DNA, or bind to p52 homodimers to coactivate transcription.…”

mentioning

confidence: 99%

“…Indeed, in the cell nucleus, Bcl-3 can either interact with suppressor p50 homodimers and remove them from DNA, or bind to p52 homodimers to coactivate transcription. [33][34][35] Furthermore, gene expression can be modulated by complex interactions of Bcl-3 with NFkB/Rel factors and other transcriptional regulators, such as histone acetylases. 36 Structural changes of nfkb1 (4q24) or relA (11q13) genes are only rarely found in leukemias, myelomas or lymphomas.…”

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confidence: 99%

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

et al. 2003

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The activity of NF-jB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfjb or ijB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-jB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-jB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-jB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NFjB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-jB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-jB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-jB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow. Regulation of apoptosis by NF-jB/Rel factors NF-kB/Rel transcription factors are dimers of proteins (p50/p105 or NF-kB1, p52/p100 or NF-kB2, p65 or RelA, c-Rel and RelB) containing an approximately 300 amino-acid REL homology domain (RHD), which mediates protein dimerization and binding to DNA. 1 The RHD is also involved in interacting with the ankyrin repeats of IkB, a family of proteins coevolved with NF-kB/Rel. 1,2 NF-kB/Rel dimers are retained in the cytoplasm of several cell types by inhibitors of the IkB family. Growth factors, cytokines, hormones or other agents can induce, through the IKK (IkB-kinase) cascade or other kinases, 1,2 the phosphorylation and ubiquitin-mediated degradation of the IkB proteins, allowing the NF-kB/Rel dimers to reach the nucleus. 3 NF-kB/Rel activation is also induced by stress stimuli that provoke increases in the intracellular concentration of reactive oxygen species (ROS), imbalance in calcium ions fluxes and/or accumulation of unfolded proteins in the endoplasmic reticulum (RE). Such events trigger the activation of stress kinases and other modulators, which ultimately lead to IkB degradation. [1][2][3]

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“…51 Furthermore, it has been shown that Bcl-3 can increase the quantity of p50 homodimers that translocate to the nucleus. 52 In light of the observations that p50 activation can be induced by Bcl-3, we tested the possible association of Bcl-3 with p50 in transactivating PTHrP. First, we studied the expression of Bcl-3 in HTLV-1-infected and ATLL cells.…”

Section: Nf-jb Regulates Pthrpmentioning

confidence: 99%

Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-κB in adult T-cell leukemia/lymphoma

et al. 2007

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Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-jB (NF-jB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Taxexpressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-jB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-jB p50/p50 alone and p50/ c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-jB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-jB activation and also suggest a Taxindependent mechanism of activation of PTHrP in ATLL.

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Regulation of NFKB1 proteins by the candidate oncoprotein BCL-3: generation of NF-kappa B homodimers from the cytoplasmic pool of p50-p105 and nuclear translocation

Cited by 105 publications

References 54 publications

Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3

Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-κB in adult T-cell leukemia/lymphoma

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