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Gene Review

Rag2  -  recombination activating gene 2

Mus musculus

Synonyms: RAG-2, Rag-2, V(D)J recombination-activating protein 2
 
 
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Disease relevance of Rag2

 

Psychiatry related information on Rag2

  • To exclude any role of host APC, MHC incompatible Rag2(- / -) mice (H-2(b)) were used as recipients for the Id(+) B and Id-specific T cells, with similar results [6].
 

High impact information on Rag2

  • Immune-deficient Rag2(-/-) mice were used as nuclear donors for transfer into enucleated oocytes, and the resulting blastocysts were cultured to isolate an isogenic embryonic stem cell line [7].
  • RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination [8].
  • RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement [9].
  • Therefore, loss of RAG-2 function in vivo results in total inability to initiate V(D)J rearrangement, leading to a novel severe combined immune deficient (SCID) phenotype [9].
  • Because the SCID phenotype was the only obvious abnormality detected in RAG-2 mutant mice, RAG-2 function and V(D)J recombinase activity, per se, are not required for development of cells other than lymphocytes [9].
 

Chemical compound and disease context of Rag2

  • The findings demonstrate that both RAG-2 SCID and B-cell-deficient mice, but not T-cell- or C5-deficient mice, have increased susceptibility to the development of disseminating anaerobic infections [10].
  • Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells [11].
  • We show that Proteus vulgaris O25 (PO25) lipopolysaccharide (LPS) induced an anaphylactoid reaction not only in wild-type and in lipid A non-responding mice but also in recombinase-activating gene-2-deficient (RAG-2(-/-)) and in mast cell-deficient (W/Wv) animals [12].
  • Liposomal mitoxantrone formulations exhibiting different drug-release characteristics were injected i.v. in mice bearing human carcinoma xenografts: A431 human squamous cell carcinoma and LS180 human colon cell carcinoma in SCID/RAG 2 mice [13].
  • High message expression by northern blotting was detected in intestine, kidney, lung, SCID, and Rag-2(-/-) thymus, and 2-deoxyguanosine-treated fetal thymic rudiment, but not in skeletal muscle, liver, heart, testis, and brain [14].
 

Biological context of Rag2

  • RORgammat expression was elevated after pre-TCR signaling, and RORgammat promoted gene rearrangement in CD4+, CD8+ cells by inhibiting cell division, promoting survival via Bcl-X(L), and inducing Rag2 [15].
  • A congenic strain (called 'ZORI' here) with defects in Rag1 and Rag2 expression, thymocyte maturation and peripheral T cell homeostasis has been developed [16].
  • Using a mouse model, we show that expression of an inducible muHC transgene in Rag2-/- pro-B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts [17].
  • It has been suggested that pre-B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele [17].
  • Using a transient transfection assay, we demonstrate that the recombination activating genes Rag1 and Rag2 direct site-specific rearrangement on an artificial substrate in poorly differentiated as well as in differentiated nonlymphoid cell lines [18].
 

Anatomical context of Rag2

 

Associations of Rag2 with chemical compounds

  • Rag2(-/-) mice reconstituted with Ppia(-/-) splenocytes were also cyclosporine resistant, indicating that this property is intrinsic to Ppia(-/-) immune cells [23].
  • We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol [24].
  • The ontogeny of B cells in the thymus of normal, CD3 epsilon knockout (KO), RAG-2 KO and IL-7 transgenic mice [25].
  • Pro-B cells from RAG2/BTK-DKO mice did not differentiate into pre-B cells following CD79b cross-linking, although tyrosine phosphorylation of cellular proteins including Erk1/2 and phospholipase C-gamma2 was induced in the same manner as RAG2-KO mice [26].
  • Moreover, in these mature lymphocyte cell lines there was no evidence of synergy in the regulation of RAG-1 and RAG-2 mRNA upon stimulation with CLA and caffeine [27].
  • Mutation of a conserved tryptophan residue in the RAG-2 PHD finger abolished binding to H3K4me3 and greatly impaired recombination of extrachromosomal and endogenous immunoglobulin gene segments [28].
 

Physical interactions of Rag2

  • Apart from showing that Sp1 interacts within the RAG-2 promoter, we also demonstrate that the Sp1-binding site is necessary for the high-level activation of this promoter [29].
  • Identification of two catalytic residues in RAG1 that define a single active site within the RAG1/RAG2 protein complex [30].
  • Inhibition of this phosphorylation by p27Kip1 stabilizes the RAG2 protein in the nucleus [31].
 

Enzymatic interactions of Rag2

 

Regulatory relationships of Rag2

  • Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3(-/-) mice to Rag2(-/-) immunodeficient mice that expressed Dsg3 [33].
  • Our work and that of others subsequently revealed that RAG-2 promoter expression is positively regulated by BSAP (PAX-5) and c-Myb transcription factors in B- and T-lineage cells, respectively [29].
  • To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice [34].
  • Injection of recombinant IL-13 induced worm expulsion in otherwise incompetent RAG2-/- mice [35].
  • Bone marrow cells from immunoglobulin HC transgenic RAG-2-/- mice have up-regulated expression of germ-line kappa LC gene transcripts and down-regulated expression of lambda 5 surrogate LCs (SLCs) [36].
 

Other interactions of Rag2

 

Analytical, diagnostic and therapeutic context of Rag2

References

  1. Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice. Rao, V.P., Poutahidis, T., Ge, Z., Nambiar, P.R., Boussahmain, C., Wang, Y.Y., Horwitz, B.H., Fox, J.G., Erdman, S.E. Cancer Res. (2006) [Pubmed]
  2. IL-4 exacerbates disease in a Th1 cell transfer model of colitis. Fort, M., Lesley, R., Davidson, N., Menon, S., Brombacher, F., Leach, M., Rennick, D. J. Immunol. (2001) [Pubmed]
  3. Early death and severe lymphopenia caused by ubiquitous expression of the Rag1 and Rag2 genes in mice. Barreto, V., Marques, R., Demengeot, J. Eur. J. Immunol. (2001) [Pubmed]
  4. Immunologic and histopathologic characterization of an active disease mouse model for pemphigus vulgaris. Ohyama, M., Amagai, M., Tsunoda, K., Ota, T., Koyasu, S., Hata, J., Umezawa, A., Nishikawa, T. J. Invest. Dermatol. (2002) [Pubmed]
  5. Polyethylene and titanium particles induce osteolysis by similar, lymphocyte-independent, mechanisms. Taki, N., Tatro, J.M., Nalepka, J.L., Togawa, D., Goldberg, V.M., Rimnac, C.M., Greenfield, E.M. J. Orthop. Res. (2005) [Pubmed]
  6. Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4(+) T cells in vivo. Munthe, L.A., Kyte, J.A., Bogen, B. Eur. J. Immunol. (1999) [Pubmed]
  7. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Rideout, W.M., Hochedlinger, K., Kyba, M., Daley, G.Q., Jaenisch, R. Cell (2002) [Pubmed]
  8. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Agrawal, A., Schatz, D.G. Cell (1997) [Pubmed]
  9. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Shinkai, Y., Rathbun, G., Lam, K.P., Oltz, E.M., Stewart, V., Mendelsohn, M., Charron, J., Datta, M., Young, F., Stall, A.M. Cell (1992) [Pubmed]
  10. B-Cell deficiency predisposes mice to disseminating anaerobic infections: protection by passive antibody transfer. Hou, L., Sasakj, H., Stashenko, P. Infect. Immun. (2000) [Pubmed]
  11. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Sánchez, C., de Ceballos, M.L., del Pulgar, T.G., Rueda, D., Corbacho, C., Velasco, G., Galve-Roperh, I., Huffman, J.W., Ramón y Cajal, S., Guzmán, M. Cancer Res. (2001) [Pubmed]
  12. Role of the complement-lectin pathway in anaphylactoid reaction induced with lipopolysaccharide in mice. Swierzko, A.S., Cedzyński, M., Kirikae, T., Nakano, M., Klink, M., Kirikae, F., Ziółkowski, A., Vinogradov, E.V., Kawakami, M. Eur. J. Immunol. (2003) [Pubmed]
  13. Role of drug release and liposome-mediated drug delivery in governing the therapeutic activity of liposomal mitoxantrone used to treat human A431 and LS180 solid tumors. Lim, H.J., Masin, D., McIntosh, N.L., Madden, T.D., Bally, M.B. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  14. Cloning and chromosomal mapping of a gene isolated from thymic stromal cells encoding a new mouse type II membrane serine protease, epithin, containing four LDL receptor modules and two CUB domains. Kim, M.G., Chen, C., Lyu, M.S., Cho, E.G., Park, D., Kozak, C., Schwartz, R.H. Immunogenetics (1999) [Pubmed]
  15. Interplay between RORgammat, Egr3, and E proteins controls proliferation in response to pre-TCR signals. Xi, H., Schwartz, R., Engel, I., Murre, C., Kersh, G.J. Immunity (2006) [Pubmed]
  16. Control of thymocyte development and recombination-activating gene expression by the zinc finger protein Zfp608. Zhang, F., Thomas, L.R., Oltz, E.M., Aune, T.M. Nat. Immunol. (2006) [Pubmed]
  17. Surface mu heavy chain signals down-regulation of the V(D)J-recombinase machinery in the absence of surrogate light chain components. Galler, G.R., Mundt, C., Parker, M., Pelanda, R., Mårtensson, I.L., Winkler, T.H. J. Exp. Med. (2004) [Pubmed]
  18. Three lymphoid-specific factors account for all junctional diversity characteristic of somatic assembly of T-cell receptor and immunoglobulin genes. Kallenbach, S., Doyen, N., Fanton d'Andon, M., Rougeon, F. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  19. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Han, S., Zheng, B., Schatz, D.G., Spanopoulou, E., Kelsoe, G. Science (1996) [Pubmed]
  20. Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes. Geiman, T.M., Muegge, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Milner, J.D., Ward, J.M., Keane-Myers, A., Paul, W.E. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  22. Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- gammac-/- mice: functional inactivation of p53 in developing T cells. Gimeno, R., Weijer, K., Voordouw, A., Uittenbogaart, C.H., Legrand, N., Alves, N.L., Wijnands, E., Blom, B., Spits, H. Blood (2004) [Pubmed]
  23. Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine. Colgan, J., Asmal, M., Yu, B., Luban, J. J. Immunol. (2005) [Pubmed]
  24. The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity. Elhage, R., Gourdy, P., Jawien, J., Brouchet, L., Castano, C., Fievet, C., Hansson, G.K., Arnal, J.F., Bayard, F. Am. J. Pathol. (2005) [Pubmed]
  25. The ontogeny of B cells in the thymus of normal, CD3 epsilon knockout (KO), RAG-2 KO and IL-7 transgenic mice. Ceredig, R. Int. Immunol. (2002) [Pubmed]
  26. Bruton's tyrosine kinase is required for signaling the CD79b-mediated pro-B to pre-B cell transition. Kouro, T., Nagata, K., Takaki, S., Nisitani, S., Hirano, M., Wahl, M.I., Witte, O.N., Karasuyama, H., Takatsu, K. Int. Immunol. (2001) [Pubmed]
  27. RAG-1 and RAG-2 gene expression and V(D)J recombinase activity are enhanced by protein phosphatase 1 and 2A inhibition in lymphocyte cell lines. Casillas, A.M., Thompson, A.D., Cheshier, S., Hernandez, S., Aguilera, R.J. Mol. Immunol. (1995) [Pubmed]
  28. A plant homeodomain in RAG-2 that binds Hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R., Desiderio, S. Immunity (2007) [Pubmed]
  29. Combinatorial regulation of the murine RAG-2 promoter by Sp1 and distinct lymphocyte-specific transcription factors. Miranda, G.A., Villalvazo, M., Galic, Z., Alva, J., Abrines, R., Yates, Y., Evans, C.J., Aguilera, R.J. Mol. Immunol. (2002) [Pubmed]
  30. Identification of two catalytic residues in RAG1 that define a single active site within the RAG1/RAG2 protein complex. Fugmann, S.D., Villey, I.J., Ptaszek, L.M., Schatz, D.G. Mol. Cell (2000) [Pubmed]
  31. RAG2 is down-regulated by cytoplasmic sequestration and ubiquitin-dependent degradation. Mizuta, R., Mizuta, M., Araki, S., Kitamura, D. J. Biol. Chem. (2002) [Pubmed]
  32. RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Chen, J., Lansford, R., Stewart, V., Young, F., Alt, F.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  33. A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice. Aoki-Ota, M., Tsunoda, K., Ota, T., Iwasaki, T., Koyasu, S., Amagai, M., Nishikawa, T. Br. J. Dermatol. (2004) [Pubmed]
  34. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. Xiao, H., Heeringa, P., Hu, P., Liu, Z., Zhao, M., Aratani, Y., Maeda, N., Falk, R.J., Jennette, J.C. J. Clin. Invest. (2002) [Pubmed]
  35. Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Barner, M., Mohrs, M., Brombacher, F., Kopf, M. Curr. Biol. (1998) [Pubmed]
  36. Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation. Young, F., Ardman, B., Shinkai, Y., Lansford, R., Blackwell, T.K., Mendelsohn, M., Rolink, A., Melchers, F., Alt, F.W. Genes Dev. (1994) [Pubmed]
  37. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Chun, J.J., Schatz, D.G., Oettinger, M.A., Jaenisch, R., Baltimore, D. Cell (1991) [Pubmed]
  38. Nuclear factor kappa B is required for the development of marginal zone B lymphocytes. Cariappa, A., Liou, H.C., Horwitz, B.H., Pillai, S. J. Exp. Med. (2000) [Pubmed]
  39. Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Petiniot, L.K., Weaver, Z., Barlow, C., Shen, R., Eckhaus, M., Steinberg, S.M., Ried, T., Wynshaw-Boris, A., Hodes, R.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  40. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Castigli, E., Alt, F.W., Davidson, L., Bottaro, A., Mizoguchi, E., Bhan, A.K., Geha, R.S. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  41. Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells. Kishi, H., Wei, X.C., Jin, Z.X., Fujishiro, Y., Nagata, T., Matsuda, T., Muraguchi, A. Blood (2000) [Pubmed]
  42. B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner. Rodríguez-Pinto, D., Moreno, J. Eur. J. Immunol. (2005) [Pubmed]
  43. A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster. Boehm, T., Gonzalez-Sarmiento, R., Kennedy, M., Rabbitts, T.H. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  44. Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency. Yates, F., Malassis-Séris, M., Stockholm, D., Bouneaud, C., Larousserie, F., Noguiez-Hellin, P., Danos, O., Kohn, D.B., Fischer, A., de Villartay, J.P., Cavazzana-Calvo, M. Blood (2002) [Pubmed]
  45. Expression of the recombinase-activating gene (RAG-1) in murine early embryogenesis. Hayakawa, S., Tochigi, M., Chishima, F., Shiraishi, H., Takahashi, N., Watanabe, K., Fujii, K.T., Satoh, K. Immunol. Cell Biol. (1996) [Pubmed]
  46. Extensive proliferation of T cell lineage-restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor beta chains. Kawamoto, H., Ohmura, K., Fujimoto, S., Lu, M., Ikawa, T., Katsura, Y. Eur. J. Immunol. (2003) [Pubmed]
 
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