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. 1997 May;17(5):2679–2687. doi: 10.1128/mcb.17.5.2679

RBP-L, a transcription factor related to RBP-Jkappa.

S Minoguchi 1, Y Taniguchi 1, H Kato 1, T Okazaki 1, L J Strobl 1, U Zimber-Strobl 1, G W Bornkamm 1, T Honjo 1
PMCID: PMC232118  PMID: 9111338

Abstract

RBP-Jkappa is a sequence-specific DNA binding protein which plays a central role in signalling downstream of the Notch receptor by physically interacting with its intracellular region. Although at least four Notch genes exist in mammals, it is unknown whether each Notch requires a specific downstream signalling molecule. Here we report isolation and characterization of a mouse RBP-Jkappa-related gene named RBP-L that is expressed almost exclusively in lung, in contrast to the ubiquitous expression of RBP-Jkappa. For simplicity, we propose to call RBP-Jkappa RBP-J. The RBP-L protein bound to a DNA sequence almost identical to that of RBP-J. Surprisingly, RBP-L did not interact with any of the known four mouse Notch proteins. Although we found that RBP-L and EBNA-2 cooperated in transcriptional activation, they did not show significantly strong protein-protein interaction that can be detected by several in vivo and in vitro assays. This is again in contrast to physical association of RBP-J with EBNA-2. Several models to explain functional interaction between RBP-L and EBNA-2 are discussed.

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Selected References

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  1. Amakawa R., Jing W., Ozawa K., Matsunami N., Hamaguchi Y., Matsuda F., Kawaichi M., Honjo T. Human Jk recombination signal binding protein gene (IGKJRB): comparison with its mouse homologue. Genomics. 1993 Aug;17(2):306–315. doi: 10.1006/geno.1993.1326. [DOI] [PubMed] [Google Scholar]
  2. Artavanis-Tsakonas S., Matsuno K., Fortini M. E. Notch signaling. Science. 1995 Apr 14;268(5208):225–232. doi: 10.1126/science.7716513. [DOI] [PubMed] [Google Scholar]
  3. Bailey A. M., Posakony J. W. Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev. 1995 Nov 1;9(21):2609–2622. doi: 10.1101/gad.9.21.2609. [DOI] [PubMed] [Google Scholar]
  4. Bettenhausen B., Hrabe de Angelis M., Simon D., Guénet J. L., Gossler A. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development. 1995 Aug;121(8):2407–2418. doi: 10.1242/dev.121.8.2407. [DOI] [PubMed] [Google Scholar]
  5. Christensen S., Kodoyianni V., Bosenberg M., Friedman L., Kimble J. lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development. 1996 May;122(5):1373–1383. doi: 10.1242/dev.122.5.1373. [DOI] [PubMed] [Google Scholar]
  6. Chung C. N., Hamaguchi Y., Honjo T., Kawaichi M. Site-directed mutagenesis study on DNA binding regions of the mouse homologue of Suppressor of Hairless, RBP-J kappa. Nucleic Acids Res. 1994 Aug 11;22(15):2938–2944. doi: 10.1093/nar/22.15.2938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen J. I., Wang F., Mannick J., Kieff E. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9558–9562. doi: 10.1073/pnas.86.23.9558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Conlon R. A., Reaume A. G., Rossant J. Notch1 is required for the coordinate segmentation of somites. Development. 1995 May;121(5):1533–1545. doi: 10.1242/dev.121.5.1533. [DOI] [PubMed] [Google Scholar]
  9. Dou S., Zeng X., Cortes P., Erdjument-Bromage H., Tempst P., Honjo T., Vales L. D. The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor. Mol Cell Biol. 1994 May;14(5):3310–3319. doi: 10.1128/mcb.14.5.3310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ellisen L. W., Bird J., West D. C., Soreng A. L., Reynolds T. C., Smith S. D., Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991 Aug 23;66(4):649–661. doi: 10.1016/0092-8674(91)90111-b. [DOI] [PubMed] [Google Scholar]
  11. Fortini M. E., Artavanis-Tsakonas S. The suppressor of hairless protein participates in notch receptor signaling. Cell. 1994 Oct 21;79(2):273–282. doi: 10.1016/0092-8674(94)90196-1. [DOI] [PubMed] [Google Scholar]
  12. Furukawa T., Kawaichi M., Matsunami N., Ryo H., Nishida Y., Honjo T. The Drosophila RBP-J kappa gene encodes the binding protein for the immunoglobulin J kappa recombination signal sequence. J Biol Chem. 1991 Dec 5;266(34):23334–23340. [PubMed] [Google Scholar]
  13. Furukawa T., Kimura K., Kobayakawa Y., Tamura K., Kawaichi M., Tanimura T., Honjo T. Genetic characterization of Drosophila RBP-J kappa (suppressor of hairless) as a neurogenic gene in adult PNS development. Jpn J Genet. 1994 Dec;69(6):701–711. doi: 10.1266/jjg.69.701. [DOI] [PubMed] [Google Scholar]
  14. Furukawa T., Kobayakawa Y., Tamura K., Kimura K., Kawaichi M., Tanimura T., Honjo T. Suppressor of hairless, the Drosophila homologue of RBP-J kappa, transactivates the neurogenic gene E(spl)m8. Jpn J Genet. 1995 Aug;70(4):505–524. doi: 10.1266/jjg.70.505. [DOI] [PubMed] [Google Scholar]
  15. Furukawa T., Maruyama S., Kawaichi M., Honjo T. The Drosophila homolog of the immunoglobulin recombination signal-binding protein regulates peripheral nervous system development. Cell. 1992 Jun 26;69(7):1191–1197. doi: 10.1016/0092-8674(92)90640-x. [DOI] [PubMed] [Google Scholar]
  16. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grossman S. R., Johannsen E., Tong X., Yalamanchili R., Kieff E. The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7568–7572. doi: 10.1073/pnas.91.16.7568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hamaguchi Y., Matsunami N., Yamamoto Y., Honjo T. Purification and characterization of a protein that binds to the recombination signal sequence of the immunoglobulin J kappa segment. Nucleic Acids Res. 1989 Nov 25;17(22):9015–9026. doi: 10.1093/nar/17.22.9015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hamaguchi Y., Yamamoto Y., Iwanari H., Maruyama S., Furukawa T., Matsunami N., Honjo T. Biochemical and immunological characterization of the DNA binding protein (RBP-J kappa) to mouse J kappa recombination signal sequence. J Biochem. 1992 Sep;112(3):314–320. doi: 10.1093/oxfordjournals.jbchem.a123898. [DOI] [PubMed] [Google Scholar]
  20. Hammerschmidt W., Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature. 1989 Aug 3;340(6232):393–397. doi: 10.1038/340393a0. [DOI] [PubMed] [Google Scholar]
  21. Henkel T., Ling P. D., Hayward S. D., Peterson M. G. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science. 1994 Jul 1;265(5168):92–95. doi: 10.1126/science.8016657. [DOI] [PubMed] [Google Scholar]
  22. Honjo T. The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells. 1996 Jan;1(1):1–9. doi: 10.1046/j.1365-2443.1996.10010.x. [DOI] [PubMed] [Google Scholar]
  23. Hsieh J. J., Hayward S. D. Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. Science. 1995 Apr 28;268(5210):560–563. doi: 10.1126/science.7725102. [DOI] [PubMed] [Google Scholar]
  24. Hsieh J. J., Henkel T., Salmon P., Robey E., Peterson M. G., Hayward S. D. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol. 1996 Mar;16(3):952–959. doi: 10.1128/mcb.16.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jarriault S., Brou C., Logeat F., Schroeter E. H., Kopan R., Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355–358. doi: 10.1038/377355a0. [DOI] [PubMed] [Google Scholar]
  26. Kang T., Martins T., Sadowski I. Wild type GAL4 binds cooperatively to the GAL1-10 UASG in vitro. J Biol Chem. 1993 May 5;268(13):9629–9635. [PubMed] [Google Scholar]
  27. Kato H., Sakai T., Tamura K., Minoguchi S., Shirayoshi Y., Hamada Y., Tsujimoto Y., Honjo T. Functional conservation of mouse Notch receptor family members. FEBS Lett. 1996 Oct 21;395(2-3):221–224. doi: 10.1016/0014-5793(96)01046-0. [DOI] [PubMed] [Google Scholar]
  28. Kopan R., Schroeter E. H., Weintraub H., Nye J. S. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683–1688. doi: 10.1073/pnas.93.4.1683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lardelli M., Dahlstrand J., Lendahl U. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev. 1994 May;46(2):123–136. doi: 10.1016/0925-4773(94)90081-7. [DOI] [PubMed] [Google Scholar]
  30. Lardelli M., Lendahl U. Motch A and motch B--two mouse Notch homologues coexpressed in a wide variety of tissues. Exp Cell Res. 1993 Feb;204(2):364–372. doi: 10.1006/excr.1993.1044. [DOI] [PubMed] [Google Scholar]
  31. Laux G., Dugrillon F., Eckert C., Adam B., Zimber-Strobl U., Bornkamm G. W. Identification and characterization of an Epstein-Barr virus nuclear antigen 2-responsive cis element in the bidirectional promoter region of latent membrane protein and terminal protein 2 genes. J Virol. 1994 Nov;68(11):6947–6958. doi: 10.1128/jvi.68.11.6947-6958.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lecourtois M., Schweisguth F. The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. Genes Dev. 1995 Nov 1;9(21):2598–2608. doi: 10.1101/gad.9.21.2598. [DOI] [PubMed] [Google Scholar]
  33. Lee N. H., Weinstock K. G., Kirkness E. F., Earle-Hughes J. A., Fuldner R. A., Marmaros S., Glodek A., Gocayne J. D., Adams M. D., Kerlavage A. R. Comparative expressed-sequence-tag analysis of differential gene expression profiles in PC-12 cells before and after nerve growth factor treatment. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8303–8307. doi: 10.1073/pnas.92.18.8303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lieber T., Kidd S., Alcamo E., Corbin V., Young M. W. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev. 1993 Oct;7(10):1949–1965. doi: 10.1101/gad.7.10.1949. [DOI] [PubMed] [Google Scholar]
  35. Lindsell C. E., Shawber C. J., Boulter J., Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell. 1995 Mar 24;80(6):909–917. doi: 10.1016/0092-8674(95)90294-5. [DOI] [PubMed] [Google Scholar]
  36. Lu F. M., Lux S. E. Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5663–5667. doi: 10.1073/pnas.93.11.5663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Matsunami N., Hamaguchi Y., Yamamoto Y., Kuze K., Kangawa K., Matsuo H., Kawaichi M., Honjo T. A protein binding to the J kappa recombination sequence of immunoglobulin genes contains a sequence related to the integrase motif. Nature. 1989 Dec 21;342(6252):934–937. doi: 10.1038/342934a0. [DOI] [PubMed] [Google Scholar]
  38. Mizushima S., Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. doi: 10.1093/nar/18.17.5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Muskavitch M. A. Delta-notch signaling and Drosophila cell fate choice. Dev Biol. 1994 Dec;166(2):415–430. doi: 10.1006/dbio.1994.1326. [DOI] [PubMed] [Google Scholar]
  40. Oka C., Nakano T., Wakeham A., de la Pompa J. L., Mori C., Sakai T., Okazaki S., Kawaichi M., Shiota K., Mak T. W. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development. 1995 Oct;121(10):3291–3301. doi: 10.1242/dev.121.10.3291. [DOI] [PubMed] [Google Scholar]
  41. Pear W. S., Aster J. C., Scott M. L., Hasserjian R. P., Soffer B., Sklar J., Baltimore D. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996 May 1;183(5):2283–2291. doi: 10.1084/jem.183.5.2283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pollock R., Treisman R. A sensitive method for the determination of protein-DNA binding specificities. Nucleic Acids Res. 1990 Nov 11;18(21):6197–6204. doi: 10.1093/nar/18.21.6197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schweisguth F., Posakony J. W. Suppressor of Hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates. Cell. 1992 Jun 26;69(7):1199–1212. doi: 10.1016/0092-8674(92)90641-o. [DOI] [PubMed] [Google Scholar]
  44. Stifani S., Blaumueller C. M., Redhead N. J., Hill R. E., Artavanis-Tsakonas S. Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins. Nat Genet. 1992 Oct;2(2):119–127. doi: 10.1038/ng1092-119. [DOI] [PubMed] [Google Scholar]
  45. Sugaya K., Fukagawa T., Matsumoto K., Mita K., Takahashi E., Ando A., Inoko H., Ikemura T. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics. 1994 Sep 15;23(2):408–419. doi: 10.1006/geno.1994.1517. [DOI] [PubMed] [Google Scholar]
  46. Swiatek P. J., Lindsell C. E., del Amo F. F., Weinmaster G., Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994 Mar 15;8(6):707–719. doi: 10.1101/gad.8.6.707. [DOI] [PubMed] [Google Scholar]
  47. Takebayashi K., Sasai Y., Sakai Y., Watanabe T., Nakanishi S., Kageyama R. Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem. 1994 Feb 18;269(7):5150–5156. [PubMed] [Google Scholar]
  48. Tamura K., Taniguchi Y., Minoguchi S., Sakai T., Tun T., Furukawa T., Honjo T. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol. 1995 Dec 1;5(12):1416–1423. doi: 10.1016/s0960-9822(95)00279-x. [DOI] [PubMed] [Google Scholar]
  49. Tun T., Hamaguchi Y., Matsunami N., Furukawa T., Honjo T., Kawaichi M. Recognition sequence of a highly conserved DNA binding protein RBP-J kappa. Nucleic Acids Res. 1994 Mar 25;22(6):965–971. doi: 10.1093/nar/22.6.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Uyttendaele H., Marazzi G., Wu G., Yan Q., Sassoon D., Kitajewski J. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development. 1996 Jul;122(7):2251–2259. doi: 10.1242/dev.122.7.2251. [DOI] [PubMed] [Google Scholar]
  51. Waltzer L., Logeat F., Brou C., Israel A., Sergeant A., Manet E. The human J kappa recombination signal sequence binding protein (RBP-J kappa) targets the Epstein-Barr virus EBNA2 protein to its DNA responsive elements. EMBO J. 1994 Dec 1;13(23):5633–5638. doi: 10.1002/j.1460-2075.1994.tb06901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Weinmaster G., Roberts V. J., Lemke G. A homolog of Drosophila Notch expressed during mammalian development. Development. 1991 Sep;113(1):199–205. doi: 10.1242/dev.113.1.199. [DOI] [PubMed] [Google Scholar]
  53. Weinmaster G., Roberts V. J., Lemke G. Notch2: a second mammalian Notch gene. Development. 1992 Dec;116(4):931–941. doi: 10.1242/dev.116.4.931. [DOI] [PubMed] [Google Scholar]
  54. Williams R., Lendahl U., Lardelli M. Complementary and combinatorial patterns of Notch gene family expression during early mouse development. Mech Dev. 1995 Nov;53(3):357–368. doi: 10.1016/0925-4773(95)00451-3. [DOI] [PubMed] [Google Scholar]
  55. Woisetschlaeger M., Jin X. W., Yandava C. N., Furmanski L. A., Strominger J. L., Speck S. H. Role for the Epstein-Barr virus nuclear antigen 2 in viral promoter switching during initial stages of infection. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3942–3946. doi: 10.1073/pnas.88.9.3942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yalamanchili R., Tong X., Grossman S., Johannsen E., Mosialos G., Kieff E. Genetic and biochemical evidence that EBNA 2 interaction with a 63-kDa cellular GTG-binding protein is essential for B lymphocyte growth transformation by EBV. Virology. 1994 Nov 1;204(2):634–641. doi: 10.1006/viro.1994.1578. [DOI] [PubMed] [Google Scholar]
  57. Zimber-Strobl U., Kremmer E., Grässer F., Marschall G., Laux G., Bornkamm G. W. The Epstein-Barr virus nuclear antigen 2 interacts with an EBNA2 responsive cis-element of the terminal protein 1 gene promoter. EMBO J. 1993 Jan;12(1):167–175. doi: 10.1002/j.1460-2075.1993.tb05642.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Zimber-Strobl U., Strobl L. J., Meitinger C., Hinrichs R., Sakai T., Furukawa T., Honjo T., Bornkamm G. W. Epstein-Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-J kappa, the homologue of Drosophila Suppressor of Hairless. EMBO J. 1994 Oct 17;13(20):4973–4982. doi: 10.1002/j.1460-2075.1994.tb06824.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. del Amo F. F., Gendron-Maguire M., Swiatek P. J., Jenkins N. A., Copeland N. G., Gridley T. Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics. 1993 Feb;15(2):259–264. doi: 10.1006/geno.1993.1055. [DOI] [PubMed] [Google Scholar]

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