Genomes and Genes
Summary: Family of retrovirus-associated DNA sequences (v-rel) originally isolated from an avian reticuloendotheliosis virus strain. The proto-oncogene rel (c-rel) codes for a subcellular (nuclear and cytoplasmic) transcription factor that has a role in lymphocyte differentiation. Translocation or overexpression of c-rel or competition from v-rel causes oncogenesis. The human rel gene is located at 2p12-13 on the short arm of chromosome 2.
- Gerdes K. Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress. J Bacteriol. 2000;182:561-72 pubmed
- Rossi D, Gaidano G. Molecular heterogeneity of diffuse large B-cell lymphoma: implications for disease management and prognosis. Hematology. 2002;7:239-52 pubmed..Overall the molecular features of DLBCL may identify prognostic categories of the disease and may represent a powerful tool for therapeutic stratification. ..
- 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. ..
- Chen Y. Genes and genomics of autoimmune inflammation: from Rel to TRAIL. Immunol Res. 2003;27:169-78 pubmed..This review will focus on two clusters of genes that we have been studying during the past few years: the Rel/nuclear factor (NF)-kappaB family and the tumor necrosis factor (TNF) family. ..
- Kralova J, Liss A, Bargmann W, Pendleton C, Varadarajan J, Ulug E, et al. Differential regulation of the inhibitor of apoptosis ch-IAP1 by v-rel and the proto-oncogene c-rel. J Virol. 2002;76:11960-70 pubmed..The ability of v-Rel to escape IkappaBalpha regulation allows for the gradual and sustained elevation of ch-IAP1 expression directly contributing to the transforming properties of v-Rel. ..
- Gilmore T, Cormier C, Jean Jacques J, Gapuzan M. Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene. 2001;20:7098-103 pubmed..These results are the first demonstration of a lymphoid cell malignant transforming ability for mammalian Rel/NF-kappaB transcription factors, and implicate c-Rel as a molecular target for cancer therapeutics. ..
- Kim Y, Han S, Ryu J, Choi K, Hong Y, Chung Y, et al. Lipopolysaccharide-activated kinase, an essential component for the induction of the antimicrobial peptide genes in Drosophila melanogaster cells. J Biol Chem. 2000;275:2071-9 pubmed..These results establish that DLAK is a novel LPS-activated kinase, which is an essential signaling component for the induction of antimicrobial peptide genes following LPS treatment in Drosophila cells. ..
- Grumont R, Strasser A, Gerondakis S. B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. Mol Cell. 2002;10:1283-94 pubmed..Collectively, these findings establish a role for Rel/NF-kappaB signaling in the mitogen-induced growth of mammalian cells, which in B lymphocytes requires a PI3K/c-myc-dependent pathway. ..
- Trynka G, Zhernakova A, Romanos J, Franke L, Hunt K, Turner G, et al. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut. 2009;58:1078-83 pubmed publisher..Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease. ..
- Hayashi M, Mizoguchi H, Ohnishi J, Mitsuhashi S, Yonetani Y, Hashimoto S, et al. A leuC mutation leading to increased L-lysine production and rel-independent global expression changes in Corynebacterium glutamicum. Appl Microbiol Biotechnol. 2006;72:783-9 pubmed..Transcriptome analysis revealed that many amino acid biosynthetic genes, including lysC-asd operon, were significantly upregulated in the leuC mutant in a rel-independent manner. ..
- Sánchez Valdepeñas C, Martin A, Ramakrishnan P, Wallach D, Fresno M. NF-kappaB-inducing kinase is involved in the activation of the CD28 responsive element through phosphorylation of c-Rel and regulation of its transactivating activity. J Immunol. 2006;176:4666-74 pubmed..This leads to more efficient transactivation of genes which are dependent on CD28RE sites where c-Rel binds such as the IL-2 promoter. ..
- Feng B, Cheng S, Hsia C, King L, Monroe J, Liou H. NF-kappaB inducible genes BCL-X and cyclin E promote immature B-cell proliferation and survival. Cell Immunol. 2004;232:9-20 pubmed..Our studies therefore suggest that specific blockade of NF-kappaB activation may be responsible for the growth arrest and apoptosis of BCR-activated immature B-cells. ..
- Shen L, Liang H, Lu F, Xu X, Li S, Hu C, et al. [Cloning and identification of NF-kappaB p50 Rel homology domain and detection of its autonomous reporter gene activity]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2004;20:419-21 pubmed..p50 RHD gene had neither autonomous reporter gene activity nor yeast cytotoxicity. As a bait plasmid, pGBKT7-p50 could be used in yeast two-hybrid system to screen and capture the polypeptides which interact with p50 RHD. ..
- Tong S, Liss A, You M, Bose H. The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation. Oncogene. 2007;26:2318-29 pubmed..These results indicate that elevated TC10 activity contributes to v-Rel-mediated transformation of CEFs and demonstrate for the first time that a Rho factor alone is capable of inducing the in vitro transformation of primary cells. ..
- Joos S, Menz C, Wrobel G, Siebert R, Gesk S, Ohl S, et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood. 2002;99:1381-7 pubmed..The imbalance pattern of cHL subtypes suggests that different molecular pathways are activated, with REL or other genes on chromosomal band 2p15-p16 playing a fundamental role in the pathogenesis of classical Hodgkin lymphoma. ..
- Hoentjen F, Sartor R, Ozaki M, Jobin C. STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood. 2005;105:689-96 pubmed..In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL-10(-/-) mice is due to enhanced NF-kappaB recruitment to the IL-12p40 promoter in the absence of activated STAT3. ..
- Barth T, Martin Subero J, Joos S, Menz C, Hasel C, Mechtersheimer G, et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood. 2003;101:3681-6 pubmed..The data suggest that REL aberrations are a genetic mechanism contributing to constitutive nuclear factor (NF)-kappa B/Rel activation in cHL...
- Nehyba J, Hrdlicková R, Burnside J, Bose H. A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein. Mol Cell Biol. 2002;22:3942-57 pubmed..Furthermore, IRF-10 expression is regulated, at least in part, by members of the Rel/NF-kappa B and IRF families. ..
- Cha Molstad H, Young D, Kushner I, Samols D. The interaction of C-Rel with C/EBPbeta enhances C/EBPbeta binding to the C-reactive protein gene promoter. Mol Immunol. 2007;44:2933-42 pubmed
- Hsia C, Cheng S, Owyang A, Dowdy S, Liou H. c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int Immunol. 2002;14:905-16 pubmed..Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response. ..
- Martin Subero J, Odero M, Hernandez R, Cigudosa J, Agirre X, Saez B, et al. Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas. Genes Chromosomes Cancer. 2005;43:414-23 pubmed..Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously. ..
- Gilmore T, Starczynowski D, Kalaitzidis D. RELevant gene amplification in B-cell lymphomas?. Blood. 2004;103:3243-4; author reply 3244-5 pubmed
- Luo W, Takakuwa T, Ham M, Wada N, Liu A, Fujita S, et al. Epstein-Barr virus is integrated between REL and BCL-11A in American Burkitt lymphoma cell line (NAB-2). Lab Invest. 2004;84:1193-9 pubmed..Integration event in NAB-2 might alter the regulation of the oncogenes and provide advantage for continuous cell proliferation. ..
- Senftleben U, Karin M. The IKK/NF-kappa B pathway. Crit Care Med. 2002;30:S18-26 pubmed
- 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. ..
- Starczynowski D, Reynolds J, Gilmore T. Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells. Oncogene. 2003;22:6928-36 pubmed
- Martin Subero J, Gesk S, Harder L, Sonoki T, Tucker P, Schlegelberger B, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood. 2002;99:1474-7 pubmed..These data indicate that REL rather than BCL11A may be the target of the 2p13 alterations in cHL. ..
- Campbell I, Gerondakis S, O DONNELL K, Wicks I. Distinct roles for the NF-kappaB1 (p50) and c-Rel transcription factors in inflammatory arthritis. J Clin Invest. 2000;105:1799-806 pubmed..Our data suggest Rel/NF-kappaB subunits play distinct roles in the pathogenesis of inflammatory arthritis and may provide a rationale for more specific therapeutic blockade of Rel/NF-kappaB in RA. ..
- Fu T, Li P, Wang H, He Y, Luo D, Zhang A, et al. c-Rel is a transcriptional repressor of EPHB2 in colorectal cancer. J Pathol. 2009;219:103-13 pubmed publisher..We demonstrate for the first time that c-Rel acts as a transcriptional repressor of EPHB2 and plays an active role in EPHB2 down-regulation in colorectal cancers. ..
- Bottex Gauthier C, Pollet S, Favier A, Vidal D. [The Rel/NF-kappa-B transcription factors: complex role in cell regulation]. Pathol Biol (Paris). 2002;50:204-11 pubmed..NF-kappa B is now regarded as a good therapeutic target and the development of specific inhibitors should lead in the next future to novel therapeutics. ..
- Zhao M, Wang Y, Murphy K, Yi J, Beckerle M, Gilmore T. LIM domain-containing protein trip6 can act as a coactivator for the v-Rel transcription factor. Gene Expr. 1999;8:207-17 pubmed
- Ramos J, Ruiz P, Ratner L, Reis I, Brites C, Pedroso C, et al. IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood. 2007;109:3060-8 pubmed..These molecular features may help guide treatment. AZT and IFN-alpha is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely. ..
- Ishii H, Takada K, Higuchi T, Sugiyama J. Verotoxin-1 induces tissue factor expression in human umbilical vein endothelial cells through activation of NF-kappaB/Rel and AP-1. Thromb Haemost. 2000;84:712-21 pubmed..The present work suggests that both the NF-kappaB/Rel and AP-1 activated in endothelial cells by stimulation with VT-1 binds to the TF-kappaB and proximal AP-1 binding sites, respectively, of the TF promoter. ..
- Graef I, Gastier J, Francke U, Crabtree G. Evolutionary relationships among Rel domains indicate functional diversification by recombination. Proc Natl Acad Sci U S A. 2001;98:5740-5 pubmed
- Torchinsky A, Toder V. To die or not to die: the function of the transcription factor NF-kappaB in embryos exposed to stress. Am J Reprod Immunol. 2004;51:138-43 pubmed
- Kang J, Jeon Y, Suh J, Park S, Yang K, Kim H. 2-Acetylaminofluorene inhibits interleukin-1beta production in LPS-stimulated macrophages by blocking NF-kappaB/Rel activation. Cancer Lett. 2004;203:91-8 pubmed..Furthermore, LPS-induced NF-kappaB/Rel DNA binding was also suppressed by AAF treatment. These results suggest that AAF inhibits IL-1beta gene expression by blocking NF-kappaB/Rel activation. ..
- Reader J, Zhao X, Butler M, Rapoport A, Ning Y. REL-positive double minute chromosomes in follicular lymphoma. Leukemia. 2006;20:1624-6 pubmed
- Garbati M, Gilmore T. Ser484 and Ser494 in REL are the major sites of IKK phosphorylation in vitro: evidence that IKK does not directly enhance GAL4-REL transactivation. Gene Expr. 2008;14:195-205 pubmed..Taken together, these results do not support a role for IKK-mediated phosphorylation as means for regulating the activity of REL in vivo. ..
- Tam W, Lee L, Davis L, Sen R. Cytoplasmic sequestration of rel proteins by IkappaBalpha requires CRM1-dependent nuclear export. Mol Cell Biol. 2000;20:2269-84 pubmed..We propose that the nucleus is the major site of p65-IkappaBalpha association, from where these complexes must be exported in order to create the cytoplasmic pool. ..
- Neiman P, Grbiç J, Polony T, Kimmel R, Bowers S, Delrow J, et al. Functional genomic analysis reveals distinct neoplastic phenotypes associated with c-myb mutation in the bursa of Fabricius. Oncogene. 2003;22:1073-86 pubmed..This functional genomic analysis uncovered several different pathways of lymphomagenesis by oncogenic transcription factors acting in a B-cell lineage...
- Ahn H, Hernandez C, Levenson J, Lubin F, Liou H, Sweatt J. c-Rel, an NF-kappaB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation. Learn Mem. 2008;15:539-49 pubmed publisher..Together, our results demonstrate that c-Rel is necessary for long-term synaptic potentiation in vitro and hippocampus-dependent memory formation in vivo. ..
- 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
- Hogan P, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17:2205-32 pubmed
- Thornburg N, Kulwichit W, Edwards R, Shair K, Bendt K, Raab Traub N. LMP1 signaling and activation of NF-kappaB in LMP1 transgenic mice. Oncogene. 2006;25:288-97 pubmed..The LMP1-mediated activation of NF-kappaB may contribute to the specific activation of c-Rel and lead to the increased development of lymphoma in the LMP1 transgenic mice. ..
- Young K, Bartlett P, Coulson E. Neural progenitor number is regulated by nuclear factor-kappaB p65 and p50 subunit-dependent proliferation rather than cell survival. J Neurosci Res. 2006;83:39-49 pubmed..No effect on cell survival was observed. This suggests that the number and fate of neural progenitor cells are more strongly regulated by cell cycle control than survival. ..
- 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. ..
- Gapuzan M, Schmah O, Pollock A, Hoffmann A, Gilmore T. Immortalized fibroblasts from NF-kappaB RelA knockout mice show phenotypic heterogeneity and maintain increased sensitivity to tumor necrosis factor alpha after transformation by v-Ras. Oncogene. 2005;24:6574-83 pubmed..These results suggest that RelA is a potential protein target for human tumors driven by oncogenic Ras mutations, but caution that inhibition of RelA may promote tumorigenesis in some circumstances. ..