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Gene Review

Rel  -  reticuloendotheliosis oncogene

Mus musculus

Synonyms: Proto-oncogene c-Rel, c-Rel
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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


Biological context of Rel


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


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


Other interactions of Rel


Analytical, diagnostic and therapeutic context of Rel


  1. Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Romieu-Mourez, R., Kim, D.W., Shin, S.M., Demicco, E.G., Landesman-Bollag, E., Seldin, D.C., Cardiff, R.D., Sonenshein, G.E. Mol. Cell. Biol. (2003) [Pubmed]
  2. Distinct roles for the NF-kappaB1 and c-Rel transcription factors in the differentiation and survival of plasmacytoid and conventional dendritic cells activated by TLR-9 signals. O'Keeffe, M., Grumont, R.J., Hochrein, H., Fuchsberger, M., Gugasyan, R., Vremec, D., Shortman, K., Gerondakis, S. Blood (2005) [Pubmed]
  3. Opposing roles for NF-kappa B/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1beta. Pizzi, M., Goffi, F., Boroni, F., Benarese, M., Perkins, S.E., Liou, H.C., Spano, P. J. Biol. Chem. (2002) [Pubmed]
  4. Divergent C-terminal transactivation domains of Rel/NF-kappa B proteins are critical determinants of their oncogenic potential in lymphocytes. Fan, Y., Rayet, B., Gélinas, C. Oncogene (2004) [Pubmed]
  5. c-Rel is essential for the development of innate and T cell-induced colitis. Wang, Y., Rickman, B.H., Poutahidis, T., Schlieper, K., Jackson, E.A., Erdman, S.E., Fox, J.G., Horwitz, B.H. J. Immunol. (2008) [Pubmed]
  6. NF-kappaB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid beta-peptide toxicity. Pizzi, M., Sarnico, I., Boroni, F., Benarese, M., Steimberg, N., Mazzoleni, G., Dietz, G.P., Bähr, M., Liou, H.C., Spano, P.F. Cell Death Differ. (2005) [Pubmed]
  7. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D.U., Jin, R., Jones, J., Cong, R., Franzoso, G. Nature (2001) [Pubmed]
  8. Structure of NF-kappa B p50 homodimer bound to a kappa B site. Ghosh, G., van Duyne, G., Ghosh, S., Sigler, P.B. Nature (1995) [Pubmed]
  9. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Sanjabi, S., Williams, K.J., Saccani, S., Zhou, L., Hoffmann, A., Ghosh, G., Gerondakis, S., Natoli, G., Smale, S.T. Genes Dev. (2005) [Pubmed]
  10. Effects of vomitoxin (deoxynivalenol) on transcription factor NF-kappa B/Rel binding activity in murine EL-4 thymoma and primary CD4+ T cells. Ouyang, Y.L., Li, S., Pestka, J.J. Toxicol. Appl. Pharmacol. (1996) [Pubmed]
  11. NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. Donovan, C.E., Mark, D.A., He, H.Z., Liou, H.C., Kobzik, L., Wang, Y., De Sanctis, G.T., Perkins, D.L., Finn, P.W. J. Immunol. (1999) [Pubmed]
  12. Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli. Mason, N., Aliberti, J., Caamano, J.C., Liou, H.C., Hunter, C.A. J. Immunol. (2002) [Pubmed]
  13. Lethal cutaneous disease in transgenic mice conditionally expressing type I human T cell leukemia virus Tax. Kwon, H., Ogle, L., Benitez, B., Bohuslav, J., Montano, M., Felsher, D.W., Greene, W.C. J. Biol. Chem. (2005) [Pubmed]
  14. Autoradiographic study of tritium-labeled misonidazole in the mouse. Cobb, L.M., Nolan, J. Int. J. Radiat. Oncol. Biol. Phys. (1989) [Pubmed]
  15. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Köntgen, F., Grumont, R.J., Strasser, A., Metcalf, D., Li, R., Tarlinton, D., Gerondakis, S. Genes Dev. (1995) [Pubmed]
  16. The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. Grumont, R., Lock, P., Mollinari, M., Shannon, F.M., Moore, A., Gerondakis, S. Immunity (2004) [Pubmed]
  17. 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. Grumont, R.J., Rourke, I.J., O'Reilly, L.A., Strasser, A., Miyake, K., Sha, W., Gerondakis, S. J. Exp. Med. (1998) [Pubmed]
  18. Cotranslational dimerization of the Rel homology domain of NF-kappaB1 generates p50-p105 heterodimers and is required for effective p50 production. Lin, L., DeMartino, G.N., Greene, W.C. EMBO J. (2000) [Pubmed]
  19. Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor. Gerondakis, S., Strasser, A., Metcalf, D., Grigoriadis, G., Scheerlinck, J.Y., Grumont, R.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  20. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. Hilliard, B.A., Mason, N., Xu, L., Sun, J., Lamhamedi-Cherradi, S.E., Liou, H.C., Hunter, C., Chen, Y.H. J. Clin. Invest. (2002) [Pubmed]
  21. Constitutive and inducible Rel/NF-kappa B activities in mouse thymus and spleen. Weih, F., Carrasco, D., Bravo, R. Oncogene (1994) [Pubmed]
  22. Conserved kappa B element located downstream of the tumor necrosis factor alpha gene: distinct NF-kappa B binding pattern and enhancer activity in LPS activated murine macrophages. Kuprash, D.V., Udalova, I.A., Turetskaya, R.L., Rice, N.R., Nedospasov, S.A. Oncogene (1995) [Pubmed]
  23. Induction of inducible nitric oxide synthase gene expression by Pokeweed mitogen. Jeon, Y.J., Lee, J.S., Jeong, H.G. Chem. Biol. Interact. (1999) [Pubmed]
  24. Role of Rel-related factors in control of c-myc gene transcription in receptor-mediated apoptosis of the murine B cell WEHI 231 line. Lee, H., Arsura, M., Wu, M., Duyao, M., Buckler, A.J., Sonenshein, G.E. J. Exp. Med. (1995) [Pubmed]
  25. Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells. Wu, M., Arsura, M., Bellas, R.E., FitzGerald, M.J., Lee, H., Schauer, S.L., Sherr, D.H., Sonenshein, G.E. Mol. Cell. Biol. (1996) [Pubmed]
  26. Distinct pathways for NF-kappa B regulation are associated with aberrant macrophage IL-12 production in lupus- and diabetes-prone mouse strains. Liu, J., Beller, D.I. J. Immunol. (2003) [Pubmed]
  27. Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter. Liu, J., Beller, D. J. Immunol. (2002) [Pubmed]
  28. A similar DNA-binding motif in NFAT family proteins and the Rel homology region. Jain, J., Burgeon, E., Badalian, T.M., Hogan, P.G., Rao, A. J. Biol. Chem. (1995) [Pubmed]
  29. Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta. Biswas, G., Anandatheerthavarada, H.K., Zaidi, M., Avadhani, N.G. J. Cell Biol. (2003) [Pubmed]
  30. B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. Grumont, R.J., Strasser, A., Gerondakis, S. Mol. Cell (2002) [Pubmed]
  31. Alternate RNA splicing of murine nfkb1 generates a nuclear isoform of the p50 precursor NF-kappa B1 that can function as a transactivator of NF-kappa B-regulated transcription. Grumont, R.J., Fecondo, J., Gerondakis, S. Mol. Cell. Biol. (1994) [Pubmed]
  32. UVB-induced association of tumor necrosis factor (TNF) receptor 1/TNF receptor-associated factor-2 mediates activation of Rel proteins. Tobin, D., van Hogerlinden, M., Toftgård, R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  33. Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-kappaB activities. Kim, D., Xu, M., Nie, L., Peng, X.C., Jimi, E., Voll, R.E., Nguyen, T., Ghosh, S., Sun, X.H. Immunity (2002) [Pubmed]
  34. Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. Grumont, R.J., Gerondakis, S. J. Exp. Med. (2000) [Pubmed]
  35. TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Belich, M.P., Salmerón, A., Johnston, L.H., Ley, S.C. Nature (1999) [Pubmed]
  36. TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Arsura, M., Wu, M., Sonenshein, G.E. Immunity (1996) [Pubmed]
  37. NF-kappa B activity is required for the deregulation of c-myc expression by the immunoglobulin heavy chain enhancer. Kanda, K., Hu, H.M., Zhang, L., Grandchamps, J., Boxer, L.M. J. Biol. Chem. (2000) [Pubmed]
  38. Developmental expression of the mouse c-rel proto-oncogene in hematopoietic organs. Carrasco, D., Weih, F., Bravo, R. Development (1994) [Pubmed]
  39. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Grumont, R.J., Rourke, I.J., Gerondakis, S. Genes Dev. (1999) [Pubmed]
  40. RelB-p50 NF-kappa B complexes are selectively induced by cytomegalovirus immediate-early protein 1: differential regulation of Bcl-x(L) promoter activity by NF-kappa B family members. Jiang, H.Y., Petrovas, C., Sonenshein, G.E. J. Virol. (2002) [Pubmed]
  41. Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor function. Bellas, R.E., Sonenshein, G.E. Cell Growth Differ. (1999) [Pubmed]
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