Disease relevance of Rel

• For example, many primary human breast cancer tissue samples express high levels of nuclear c-Rel [1].
• Reticuloendotheliosis viral oncogene homolog/nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Rel/NF-kappaB) activation is a ubiquitous outcome of engaging Toll-like receptors (TLRs), yet the cell-type-specific functions of this pathway in response to particular microbial signals remain poorly defined [2].
• To directly test the role of c-Rel in breast tumorigenesis, mice were generated in which overexpression of mouse c-rel cDNA was driven by the hormone-responsive mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter, and four founder lines identified [1].
• In both cultured rat cerebellar granule cells and mouse hippocampal slices, we examined NF-kappaB/Rel activation induced by two opposing modulators of cell viability: 1) interleukin-1beta (IL-1beta), which promotes neuron survival and 2) glutamate, which can elicit toxicity [3].
• These findings provide experimental evidence for a role of mammalian Rel/NF-kappaB factors in leukemia/lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas [4].
• We have found that the absence of c-Rel significantly impaired the ability of Helicobacter hepaticus to induce colitis upon infection of RAG-2-deficient mice, and ameliorated the ability of CD4(+)CD45RB(high) T cells to induce disease upon adoptive transfer into RAG-deficient mice [5].

Psychiatry related information on Rel

• However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-beta (Abeta), a peptide implicated in Alzheimer's disease pathogenesis [6].

High impact information on Rel

• In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival [7].
• The carboxy-terminal domains form a dimerization interface between beta-sheets using residues that are strongly conserved in the Rel family [8].
• Here we demonstrate that 46 unique residues within an 86-residue segment of the Rel homology region (RHR) of c-Rel are responsible for the c-Rel requirement for Il12b gene induction by lipopolysaccharide in bone marrow-derived macrophages [9].
• These same residues were responsible for the c-Rel requirement for Il12a induction in dendritic cells, and in both instances, no evidence of c-Rel-specific coactivator interactions was found [9].
• A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation [9].

Chemical compound and disease context of Rel

• When EL-4 thymoma cells were stimulated with phorbol 12-myristate 13-acetate plus ionomycin in the presence of 500 ng/ml VT, DNA binding activity by NF-kappaB/Rel in nuclear extracts was increased from 2 to 48 hr when compared to controls employing no VT [10].
• We tested whether c-Rel promotes allergic asthma using a murine model of allergen-induced pulmonary inflammation and airway hyperresponsiveness [11].
• In this study, we demonstrate that c-Rel is also required for IL-12p40 production by macrophages in response to Corynebacterium parvum, CpG oligodeoxynucleotides, anti-CD40 and low molecular weight hyaluronic acid [12].
• Tax both stimulates the HTLV-I long terminal repeat and deregulates the expression of select cellular genes by altering the activity of specific host transcription factors, including cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor, NF-kappaB/Rel, and serum response factor [13].
• The labeled misonidazole was injected at 750 or 75 mg/kg body weight (Rel. Sp. Act. 74 and 740 MBq/mg respectively) [14].

Biological context of Rel

• The ability of exogenous interleukin-2 to restore T Cell, but not B cell, proliferation indicates that Rel regulates the expression of different genes in B and T cells that are crucial for cell division and immune function [15].
• Cell growth during the G1 stage of the cell cycle is partly controlled by inducing c-myc expression, which in B cells is regulated by the NF-kappaB1 and c-Rel transcription factors [16].
• B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells [17].
• We now demonstrate that the Rel homology domain in p50 undergoes cotranslational dimerization and that this interaction is required for efficient production of p50 [18].
• In an attempt to identify changes in gene expression that accompany the T-cell stimulation defects associated with the loss of Rel, we have examined the expression of cell surface activation markers and cytokine production in mitogen-stimulated Rel-/- T cells [19].

Anatomical context of Rel

• Phorbol ester and calcium ionophore costimulation, in contrast to certain membrane receptor-mediated signals, overcame the T cell-proliferative defect, demonstrating that T cell proliferation occurs by Rel-dependent and -independent mechanisms [15].
• Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation [20].
• In transient transfection analysis in untransformed breast epithelial cells, c-Rel-p52 or -p50 heterodimers either potently or modestly induced cyclin D1 promoter activity, respectively [1].
• Divergent C-terminal transactivation domains of Rel/NF-kappa B proteins are critical determinants of their oncogenic potential in lymphocytes [4].
• Treatment of thymus and spleen extracts with deoxycholate (DOC), however, results in a strong increase in binding to kappa B sites of both RelA and c-Rel complexes [21].

Associations of Rel with chemical compounds

• Glutamate produced a delayed and transient activation of NF-kappaB/Rel, which was associated with a brief loss of IkappaBalpha [3].
• The appearance of complex III in EMSA parallels the translocation of p65 and c-Rel into the nucleus and occurs shortly after LPS induction [22].
• N-Tosyl-1-phenylalanine chloromethyl ketone, a potent inhibitor of NF-kappaB/Rel activation, inhibited PWM-induced nitrite generation in a dose-dependent manner [23].
• The role of activation of Rel-family binding was demonstrated directly upon addition of the antioxidant pyrrolidinedithiocarbamate, which inhibited the anti-sIg-mediated activation of the endogenous c-myc gene [24].
• Addition of the serine/threonine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), which blocks the normally rapid turnover of the specific inhibitor of NF-kappaB/Rel IkappaBalpha in these cells, caused a drop in Rel-related factor binding [25].

Physical interactions of Rel

• Mechanistically, the abnormal regulation of IL-12 in these strains was found to be strictly associated with novel patterns of Rel binding in vitro to the unique NF-kappaB site in the IL-12 p40 promoter [26].
• Evaluation of the possible mechanism(s) underlying the abnormal regulation of IL-12 in these strains revealed novel patterns of Rel family protein binding to the unique p40 NF-kappaB site in the IL-12 p40 promoter, whereas binding patterns to Ets and CCAAT enhancer binding protein/beta sites were normal [27].
• Treatment with anti-sIg resulted in a rapid transient increase in the rate of c-myc gene transcription and in the binding of Rel factors [24].
• Mutational analysis demonstrates that the residues in this sequence that are identical in NFATp and Rel family proteins contribute to DNA binding by NFATp [28].
• Chemical cross-linking and coimmunoprecipitation show that NFkappaB/Rel factor-bound IkappaBbeta forms a ternary complex with Cn under in vitro and in vivo conditions that was sensitive to FK506 [29].

Regulatory relationships of Rel

• Here we show that B cells lacking NF-kappaB1 and c-Rel fail to increase in size upon mitogenic stimulation due to a reduction in induced c-myc expression [30].
• Transient transfection analysis revealed that p98NF-kappa B1, but not p105NF-kappa B1 or p84NF-kappa B1, acts as a transactivator of NF-kappa B-regulated gene expression and that this is dependent on sequences in the Rel homology domain required for DNA binding and on the novel 35 C-terminal aa of this isoform [31].
• The functional relevance of this association is demonstrated by experiments showing that expression of a dominant negative TNF receptor 1 or TRAF-2 protein inhibits UVB-induced Rel-dependent transcription [32].
• Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-kappaB activities [33].
• Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB [34].

Other interactions of Rel

• Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus [35].
• B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription [30].
• Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor [19].
• Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression [15].
• A reduction in NF-kappa B/Rel activity followed TGF beta 1 treatment [36].

Analytical, diagnostic and therapeutic context of Rel

• Electrophoretic mobility shift assay analysis revealed that NF-kappaB/Rel family members bound to this region [37].
• We have studied the expression of the c-rel proto-oncogene during mouse embryonic development and adult animals using in situ hybridization and immunocytochemical analysis. c-rel transcripts were detected late in development with an expression pattern that parallels the emergence and diversification of hematopoietic cells [38].
• In B-cell lines derived from c-rel-/- mice, which like primary cells lacking Rel undergo apoptosis in response to antigen receptor ligation, constitutive expression of an A1 transgene inhibits this pathway to cell death [39].
• Thus, the subunit nature of the NF-kappa B/Rel factors induced by IE1 was examined using immunofluorescence and immunoblotting [40].
• Inhibition of NF-kappaB/Rel activity by microinjection of the specific inhibitor IkappaB-alpha induces apoptosis in a nontransformed normal murine hepatocyte (NMH) cell line [41].

References