Genomes and Genes
proto oncogene proteins c rel
Summary: Cellular DNA-binding proteins encoded by the rel gene (GENES, REL). They are expressed predominately in hematopoietic cells and may play a role in lymphocyte differentiation. Rel frequently combines with other related proteins (NF-KAPPA B, I-kappa B, relA) to form heterodimers that regulate transcription. Rearrangement or overexpression of c-rel can cause tumorigenesis.
- La Rosa F, Pierce J, Sonenshein G. Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors. Mol Cell Biol. 1994;14:1039-44 pubmed..Thus, individual members of the rel family have differential effects of the c-myc promoter, which can modulate overall transcriptional activity and allow for precise regulation of this oncogene under diverse physiologic conditions. ..
- Harling McNabb L, Deliyannis G, Jackson D, Gerondakis S, Grigoriadis G, Brown L. Mice lacking the transcription factor subunit Rel can clear an influenza infection and have functional anti-viral cytotoxic T cells but do not develop an optimal antibody response. Int Immunol. 1999;11:1431-9 pubmed..These findings establish that during the response to influenza virus, Rel function allows optimal development of humoral immunity, a role that apparently cannot be fulfilled by other NF-kappaB/Rel proteins. ..
- Starczynowski D, Trautmann H, Pott C, Harder L, Arnold N, Africa J, et al. Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity. Oncogene. 2007;26:2685-94 pubmed..These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL. ..
- Klement J, Rice N, Car B, Abbondanzo S, Powers G, Bhatt P, et al. IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Mol Cell Biol. 1996;16:2341-9 pubmed..An increased percentage of monocytes/macrophages was detected in spleen cells taken from 5-, 7-, and 9-day-old pups. Death is accompanied by severe widespread dermatitis and increased levels of TNF-alpha mRNA in the skin. ..
- Weih F, Carrasco D, Bravo R. Constitutive and inducible Rel/NF-kappa B activities in mouse thymus and spleen. Oncogene. 1994;9:3289-97 pubmed
- Carmody R, Ruan Q, Liou H, Chen Y. Essential roles of c-Rel in TLR-induced IL-23 p19 gene expression in dendritic cells. J Immunol. 2007;178:186-91 pubmed..Based on these observations, we conclude that c-Rel controls IL-23 p19 gene expression through two kappaB sites in the p19 promoter, and propose a c-Rel-dependent enhanceosome model for p19 gene activation. ..
- Sha W, Liou H, Tuomanen E, Baltimore D. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell. 1995;80:321-30 pubmed..These data support the role of NF-kappa B as a vital transcription factor for both specific and nonspecific immune responses, but do not indicate a developmental role for the factor. ..
- Bull P, Morley K, Hoekstra M, Hunter T, Verma I. The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain. Mol Cell Biol. 1990;10:5473-85 pubmed..We propose that c-rel protein has an N-terminal regulatory domain and a C-terminal transactivation domain which together modulate its function as a transcriptional transactivator. ..
- Owyang A, Tumang J, Schram B, Hsia C, Behrens T, Rothstein T, et al. c-Rel is required for the protection of B cells from antigen receptor-mediated, but not Fas-mediated, apoptosis. J Immunol. 2001;167:4948-56 pubmed..Thus, c-Rel is dispensable for protection against death receptor-mediated apoptosis. Taken together, our data suggest that distinct NF-kappaB/Rel members are required for protecting cells from different types of apoptotic signals. ..
- Grumont R, Hochrein H, O KEEFFE M, Gugasyan R, White C, Caminschi I, et al. c-Rel regulates interleukin 12 p70 expression in CD8(+) dendritic cells by specifically inducing p35 gene transcription. J Exp Med. 2001;194:1021-32 pubmed
- Zheng Y, Ouaaz F, Bruzzo P, Singh V, Gerondakis S, Beg A. NF-kappa B RelA (p65) is essential for TNF-alpha-induced fas expression but dispensable for both TCR-induced expression and activation-induced cell death. J Immunol. 2001;166:4949-57 pubmed
- Mason N, Aliberti J, Caamano J, Liou H, Hunter C. Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli. J Immunol. 2002;168:2590-4 pubmed..Together these studies reveal the presence of c-Rel-dependent pathways critical for IL-12p40 production in response to inflammatory stimuli and demonstrate a novel c-Rel-independent pathway of IL-12p40 production during toxoplasmosis. ..
- Rao S, Gerondakis S, Woltring D, Shannon M. c-Rel is required for chromatin remodeling across the IL-2 gene promoter. J Immunol. 2003;170:3724-31 pubmed..These results suggest a nonredundant role for c-Rel in generating a correctly remodeled chromatin state across the IL-2 promoter and imply that the strength of the signal determines the requirement for c-Rel. ..
- Joos S, Granzow M, Holtgreve Grez H, Siebert R, Harder L, Martin Subero J, et al. Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int J Cancer. 2003;103:489-95 pubmed
- Liou H, Jin Z, Tumang J, Andjelic S, Smith K, Liou M. c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. Int Immunol. 1999;11:361-71 pubmed..These data suggest that c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. ..
- Pohl T, Gugasyan R, Grumont R, Strasser A, Metcalf D, Tarlinton D, et al. The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc Natl Acad Sci U S A. 2002;99:4514-9 pubmed..These findings demonstrate that in the B lineage overlapping roles for NF-kappaB1 and c-Rel appear to be restricted to regulating the activation and function of mature cells. ..
- Mintern J, Belz G, Gerondakis S, Carbone F, Heath W. The cross-priming APC requires a Rel-dependent signal to induce CTL. J Immunol. 2002;168:3283-7 pubmed..The first signal is Rel dependent and is required before activation of CD4 helper T cells, which then deliver the second signal using CD154 to trigger CD40. ..
- Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938-47 pubmed..This review focuses on the status of the rel, nfkb and ikb genes and their activity in human tumors and their association with the onset or progression of malignancies. ..
- O Connor S, Shumway S, Amanna I, Hayes C, Miyamoto S. Regulation of constitutive p50/c-Rel activity via proteasome inhibitor-resistant IkappaBalpha degradation in B cells. Mol Cell Biol. 2004;24:4895-908 pubmed..Thus, our findings suggest that nonconventional PIR degradation of IkappaBalpha may play a physiological role in the development of B cells in vivo. ..
- Cheng S, Hsia C, Leone G, Liou H. Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel-/- B cells. Oncogene. 2003;22:8472-86 pubmed
- Grumont R, Lock P, Mollinari M, Shannon F, Moore A, Gerondakis S. The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. Immunity. 2004;21:19-30 pubmed
- Starczynowski D, Reynolds J, Gilmore T. Mutations of tumor necrosis factor alpha-responsive serine residues within the C-terminal transactivation domain of human transcription factor REL enhance its in vitro transforming ability. Oncogene. 2005;24:7355-68 pubmed..Lastly, these results suggest that similar mutations in the REL transactivation domain contribute to the development of certain human B-cell lymphomas. ..
- Huang D, Chen Y, Ruetsche M, Phelps C, Ghosh G. X-ray crystal structure of proto-oncogene product c-Rel bound to the CD28 response element of IL-2. Structure. 2001;9:669-78 pubmed..Two amino acid changes in these segments may account for the differential DNA binding by v-Rel as compared to that of c-Rel. ..
- Banerjee D, Liou H, Sen R. c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity. 2005;23:445-58 pubmed..This mechanism does not operate in effector T cells where cytokine gene expression is c-Rel-independent. We propose that c-Rel plays a crucial role as a target of innate signals in T cells. ..
- Kim D, Xu M, Nie L, PENG X, Jimi E, Voll R, et al. Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-kappaB activities. Immunity. 2002;16:9-21 pubmed..Therefore, we propose that E2A and HEB negatively regulate pre-TCR and TCR signaling and their removal causes hyperactivation and apoptosis of thymocytes. ..
- Gugasyan R, Voss A, Varigos G, Thomas T, Grumont R, Kaur P, et al. The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Mol Cell Biol. 2004;24:5733-45 pubmed
- Houldsworth J, Olshen A, Cattoretti G, Donnelly G, Teruya Feldstein J, Qin J, et al. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas. Blood. 2004;103:1862-8 pubmed..Nonetheless, these data indicate that DLBCLs are heterogeneous with respect to REL and thus nuclear factor-kappaB (NF-kappaB) activity. ..
- Zarnegar B, He J, Oganesyan G, Hoffmann A, Baltimore D, Cheng G. Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways. Proc Natl Acad Sci U S A. 2004;101:8108-13 pubmed..Overall, our studies suggest that both type 1 and type 2 NF-kappaB pathways contribute to the gene expression and biological program unique for CD40 in B cell activation. ..
- Nolan G, Ghosh S, Liou H, Tempst P, Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell. 1991;64:961-9 pubmed
- Dai R, Phillips R, Ahmed S. Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3. J Immunol. 2007;179:1776-83 pubmed..The novel findings of differential regulation of NF-kappaB proteins by estrogen provide fresh insight into potential mechanisms by which estrogen can regulate NF-kappaB-dependent immunological events. ..
- Yang H, Thomas D, Boffa D, Ding R, Li B, Muthukumar T, et al. Enforced c-REL deficiency prolongs survival of islet allografts1. Transplantation. 2002;74:291-8 pubmed
- Kalaitzidis D, Gilmore T. Genomic organization and expression of the rearranged REL proto-oncogene in the human B-cell lymphoma cell line RC-K8. Genes Chromosomes Cancer. 2002;34:129-35 pubmed..Furthermore, like c-Rel, c-Rel-Nrg is a cytoplasmic protein when overexpressed in fibroblasts in culture and can bind to a kappaB DNA site in vitro. ..
- Ouaaz F, Arron J, Zheng Y, Choi Y, Beg A. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity. 2002;16:257-70 pubmed..These results therefore indicate essential, subunit-specific functions for NF-kappaB proteins in regulating DC development, survival, and cytokine production. ..
- Lu D, Thompson J, Gorski G, Rice N, Mayer M, Yunis J. Alterations at the rel locus in human lymphoma. Oncogene. 1991;6:1235-41 pubmed..In addition, rearrangement or amplification of the rel locus was found in the lymphomatous tissue of two follicular and one diffuse large cell lymphoma. The findings suggest involvement of rel in the pathogenesis of large cell lymphoma. ..
- Kontgen F, Grumont R, Strasser A, Metcalf D, Li R, Tarlinton D, et al. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995;9:1965-77 pubmed..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. ..
- Strasser A, Grumont R, Stanley M, Gerondakis S. The transcriptional regulator Rel is essential for antigen receptor-mediated stimulation of mature T cells but dispensable for positive and negative selection of thymocytes and T cell apoptosis. Eur J Immunol. 1999;29:928-35 pubmed..These results indicate that thymocytes and mature T cells differ in their requirement for Rel in mediating TCR-induced responses. ..
- Tumang J, Hsia C, Tian W, Bromberg J, Liou H. IL-6 rescues the hyporesponsiveness of c-Rel deficient B cells independent of Bcl-xL, Mcl-1, and Bcl-2. Cell Immunol. 2002;217:47-57 pubmed..Together, these data demonstrate that IL-6 enhances B cell responses by employing multiple survival factors. ..
- Whiteside S, Epinat J, Rice N, Israel A. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J. 1997;16:1413-26 pubmed..I kappa B-epsilon would, therefore, appear to regulate a late, transient activation of a subset of genes, regulated by RelA/cRel NF-kappa B complexes, distinct from those regulated by other I kappa B proteins. ..
- Cramer P, Larson C, Verdine G, Muller C. Structure of the human NF-kappaB p52 homodimer-DNA complex at 2.1 A resolution. EMBO J. 1997;16:7078-90 pubmed..The observed water network might acount for differences in binding specificity between NF-kappaB p52 and NF-kappaB p50 homodimers. ..
- Tumang J, Owyang A, Andjelic S, Jin Z, Hardy R, Liou M, et al. c-Rel is essential for B lymphocyte survival and cell cycle progression. Eur J Immunol. 1998;28:4299-312 pubmed..Furthermore, while c-Rel is involved in CD40-induced proliferation, it is apparently dispensable for the survival signals transduced by CD40. ..
- Grossmann M, Metcalf D, Merryfull J, Beg A, Baltimore D, Gerondakis S. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci U S A. 1999;96:11848-53 pubmed
- Fan Y, Rayet B, Gelinas C. Divergent C-terminal transactivation domains of Rel/NF-kappa B proteins are critical determinants of their oncogenic potential in lymphocytes. Oncogene. 2004;23:1030-42 pubmed..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. ..
- Martin A, San Antonio B, Fresno M. Regulation of nuclear factor kappa B transactivation. Implication of phosphatidylinositol 3-kinase and protein kinase C zeta in c-Rel activation by tumor necrosis factor alpha. J Biol Chem. 2001;276:15840-9 pubmed..Interestingly, those c-Rel mutants not only did not respond to TNFalpha but also acted as dominant negative forms of nuclear factor kappaB activation. ..
- Lamhamedi Cherradi S, Zheng S, Hilliard B, Xu L, Sun J, Alsheadat S, et al. Transcriptional regulation of type I diabetes by NF-kappa B. J Immunol. 2003;171:4886-92 pubmed..These results indicate that both c-Rel and NF-kappaB1are essential for the development of type I diabetes and that strategies targeting each of these subunits would be effective in preventing the disease. ..
- Yamada T, Mitani T, Yorita K, Uchida D, Matsushima A, Iwamasa K, et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase. J Immunol. 2000;165:804-12 pubmed..Thus, the aly NIK mutation affects hemopoietic cell function in an intrinsic fashion and, together with the stromal defect, may contribute to the development of immunodeficiency in aly mice. ..
- O Keeffe M, Grumont R, Hochrein H, Fuchsberger M, Gugasyan R, Vremec D, et al. 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. Blood. 2005;106:3457-64 pubmed..Collectively, these findings establish that NF-kappaB1 and c-Rel, while largely dispensable for TLR-9-induced cDC activation, are critical for regulating differentiation and survival programs during pDC activation. ..
- Sanjabi S, Williams K, Saccani S, Zhou L, Hoffmann A, Ghosh G, et al. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Genes Dev. 2005;19:2138-51 pubmed
- Grumont R, Rourke I, O Reilly L, Strasser A, Miyake K, Sha W, et al. 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. J Exp Med. 1998;187:663-74 pubmed
- Thompson J, Phillips R, Erdjument Bromage H, Tempst P, Ghosh S. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell. 1995;80:573-82 pubmed..Therefore, the overall activation of NF-kappa B consists of two overlapping phases, a transient phase mediated through I kappa B-alpha and a persistent phase mediated through I kappa B-beta. ..
- Liou H, Hsia C. Distinctions between c-Rel and other NF-kappaB proteins in immunity and disease. Bioessays. 2003;25:767-80 pubmed..The study of c-Rel knockout mice in several disease models will also be discussed as they reveal an important role for c-Rel in response to allergens, auto-antigens, allo-antigens and pathogenic infection. ..
- Zheng Y, Vig M, Lyons J, Van Parijs L, Beg A. Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med. 2003;197:861-74 pubmed..These findings provide the first demonstration of a role for NF-kappaB proteins in regulating T cell function in vivo and establish a critically important function of NF-kappaB in TCR-induced regulation of survival. ..
- Chen X, Kandasamy K, Srivastava R. Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 2003;63:1059-66 pubmed..Thus, NF-kappa B activity may play an important role in tumor progression, and down-regulation of RelA or up-regulation of c-Rel represents a possible therapeutic target for the treatment of cancer. ..