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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Jul 9;93(14):6947–6952. doi: 10.1073/pnas.93.14.6947

BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor.

C C Chang 1, B H Ye 1, R S Chaganti 1, R Dalla-Favera 1
PMCID: PMC38914  PMID: 8692924

Abstract

Approximately 40% of diffuse large cell lymphoma are associated with chromosomal translocations that deregulate the expression of the BCL6 gene by juxtaposing heterologous promoters to the BCL-6 coding domain. The BCL6 gene encodes a 95-kDa protein containing six C-terminal zinc-finger motifs and an N-terminal POZ domain, suggesting that it may function as a transcription factor. By using a DNA sequence selected for its ability to bind recombinant BCL-6 in vitro, we show here that BCL-6 is present in DNA-binding complexes in nuclear extracts from various B-cell lines. In transient transfectin experiments, BCL6 can repress transcription from promoters linked to its DNA target sequence and this activity is dependent upon specific DNA-binding and the presence of an intact N-terminal half of the protein. We demonstrate that this part of the BCL6 molecule contains an autonomous transrepressor domain and that two noncontiguous regions, including the POZ motif, mediate maximum transrepressive activity. These results indicate that the BCL-6 protein can function as a sequence-specific transcriptional repressor and have implications for the role of BCL6 in normal lymphoid development and lymphomagenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albagli O., Dhordain P., Deweindt C., Lecocq G., Leprince D. The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. Cell Growth Differ. 1995 Sep;6(9):1193–1198. [PubMed] [Google Scholar]
  2. Bardwell V. J., Treisman R. The POZ domain: a conserved protein-protein interaction motif. Genes Dev. 1994 Jul 15;8(14):1664–1677. doi: 10.1101/gad.8.14.1664. [DOI] [PubMed] [Google Scholar]
  3. Baron B. W., Nucifora G., McCabe N., Espinosa R., 3rd, Le Beau M. M., McKeithan T. W. Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5262–5266. doi: 10.1073/pnas.90.11.5262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baron B. W., Stanger R. R., Hume E., Sadhu A., Mick R., Kerckaert J. P., Deweindt C., Bastard C., Nucifora G., Zeleznik-Le N. BCL6 encodes a sequence-specific DNA-binding protein. Genes Chromosomes Cancer. 1995 Jul;13(3):221–224. doi: 10.1002/gcc.2870130314. [DOI] [PubMed] [Google Scholar]
  5. Bastard C., Deweindt C., Kerckaert J. P., Lenormand B., Rossi A., Pezzella F., Fruchart C., Duval C., Monconduit M., Tilly H. LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood. 1994 May 1;83(9):2423–2427. [PubMed] [Google Scholar]
  6. Cattoretti G., Chang C. C., Cechova K., Zhang J., Ye B. H., Falini B., Louie D. C., Offit K., Chaganti R. S., Dalla-Favera R. BCL-6 protein is expressed in germinal-center B cells. Blood. 1995 Jul 1;86(1):45–53. [PubMed] [Google Scholar]
  7. Chang C. C., Zhang J., Lombardi L., Neri A., Dalla-Favera R. Rearranged NFKB-2 genes in lymphoid neoplasms code for constitutively active nuclear transactivators. Mol Cell Biol. 1995 Sep;15(9):5180–5187. doi: 10.1128/mcb.15.9.5180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chardin P., Courtois G., Mattei M. G., Gisselbrecht S. The KUP gene, located on human chromosome 14, encodes a protein with two distant zinc fingers. Nucleic Acids Res. 1991 Apr 11;19(7):1431–1436. doi: 10.1093/nar/19.7.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen W., Zollman S., Couderc J. L., Laski F. A. The BTB domain of bric à brac mediates dimerization in vitro. Mol Cell Biol. 1995 Jun;15(6):3424–3429. doi: 10.1128/mcb.15.6.3424. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  10. Chen Z., Brand N. J., Chen A., Chen S. J., Tong J. H., Wang Z. Y., Waxman S., Zelent A. Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J. 1993 Mar;12(3):1161–1167. doi: 10.1002/j.1460-2075.1993.tb05757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cowell I. G. Repression versus activation in the control of gene transcription. Trends Biochem Sci. 1994 Jan;19(1):38–42. doi: 10.1016/0968-0004(94)90172-4. [DOI] [PubMed] [Google Scholar]
  12. Dalla-Favera R., Ye B. H., Lo Coco F., Chang C. C., Cechova K., Zhang J., Migliazza A., Mellado W., Niu H., Chaganti S. BCL-6 and the molecular pathogenesis of B-cell lymphoma. Cold Spring Harb Symp Quant Biol. 1994;59:117–123. doi: 10.1101/sqb.1994.059.01.015. [DOI] [PubMed] [Google Scholar]
  13. Deweindt C., Albagli O., Bernardin F., Dhordain P., Quief S., Lantoine D., Kerckaert J. P., Leprince D. The LAZ3/BCL6 oncogene encodes a sequence-specific transcriptional inhibitor: a novel function for the BTB/POZ domain as an autonomous repressing domain. Cell Growth Differ. 1995 Dec;6(12):1495–1503. [PubMed] [Google Scholar]
  14. DiBello P. R., Withers D. A., Bayer C. A., Fristrom J. W., Guild G. M. The Drosophila Broad-Complex encodes a family of related proteins containing zinc fingers. Genetics. 1991 Oct;129(2):385–397. doi: 10.1093/genetics/129.2.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Flenghi L., Ye B. H., Fizzotti M., Bigerna B., Cattoretti G., Venturi S., Pacini R., Pileri S., Lo Coco F., Pescarmona E. A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells. Am J Pathol. 1995 Aug;147(2):405–411. [PMC free article] [PubMed] [Google Scholar]
  16. Giniger E., Varnum S. M., Ptashne M. Specific DNA binding of GAL4, a positive regulatory protein of yeast. Cell. 1985 Apr;40(4):767–774. doi: 10.1016/0092-8674(85)90336-8. [DOI] [PubMed] [Google Scholar]
  17. Gregory C. D., Rowe M., Rickinson A. B. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol. 1990 Jul;71(Pt 7):1481–1495. doi: 10.1099/0022-1317-71-7-1481. [DOI] [PubMed] [Google Scholar]
  18. Harrison S. D., Travers A. A. The tramtrack gene encodes a Drosophila finger protein that interacts with the ftz transcriptional regulatory region and shows a novel embryonic expression pattern. EMBO J. 1990 Jan;9(1):207–216. doi: 10.1002/j.1460-2075.1990.tb08097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kawamata N., Miki T., Ohashi K., Suzuki K., Fukuda T., Hirosawa S., Aoki N. Recognition DNA sequence of a novel putative transcription factor, BCL6. Biochem Biophys Res Commun. 1994 Oct 14;204(1):366–374. doi: 10.1006/bbrc.1994.2468. [DOI] [PubMed] [Google Scholar]
  20. Kerckaert J. P., Deweindt C., Tilly H., Quief S., Lecocq G., Bastard C. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet. 1993 Sep;5(1):66–70. doi: 10.1038/ng0993-66. [DOI] [PubMed] [Google Scholar]
  21. Koonin E. V., Senkevich T. G., Chernos V. I. A family of DNA virus genes that consists of fused portions of unrelated cellular genes. Trends Biochem Sci. 1992 Jun;17(6):213–214. doi: 10.1016/0968-0004(92)90379-n. [DOI] [PubMed] [Google Scholar]
  22. Lillie J. W., Green M. R. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. doi: 10.1038/338039a0. [DOI] [PubMed] [Google Scholar]
  23. Liu Q., Shalaby F., Puri M. C., Tang S., Breitman M. L. Novel zinc finger proteins that interact with the mouse gamma F-crystallin promoter and are expressed in the sclerotome during early somitogenesis. Dev Biol. 1994 Sep;165(1):165–177. doi: 10.1006/dbio.1994.1243. [DOI] [PubMed] [Google Scholar]
  24. Lo Coco F., Ye B. H., Lista F., Corradini P., Offit K., Knowles D. M., Chaganti R. S., Dalla-Favera R. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Blood. 1994 Apr 1;83(7):1757–1759. [PubMed] [Google Scholar]
  25. Madden S. L., Cook D. M., Rauscher F. J., 3rd A structure-function analysis of transcriptional repression mediated by the WT1, Wilms' tumor suppressor protein. Oncogene. 1993 Jul;8(7):1713–1720. [PubMed] [Google Scholar]
  26. Migliazza A., Martinotti S., Chen W., Fusco C., Ye B. H., Knowles D. M., Offit K., Chaganti R. S., Dalla-Favera R. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12520–12524. doi: 10.1073/pnas.92.26.12520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miki T., Kawamata N., Hirosawa S., Aoki N. Gene involved in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes a Krüppel-like zinc-finger protein. Blood. 1994 Jan 1;83(1):26–32. [PubMed] [Google Scholar]
  28. Numoto M., Niwa O., Kaplan J., Wong K. K., Merrell K., Kamiya K., Yanagihara K., Calame K. Transcriptional repressor ZF5 identifies a new conserved domain in zinc finger proteins. Nucleic Acids Res. 1993 Aug 11;21(16):3767–3775. doi: 10.1093/nar/21.16.3767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Onizuka T., Moriyama M., Yamochi T., Kuroda T., Kazama A., Kanazawa N., Sato K., Kato T., Ota H., Mori S. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood. 1995 Jul 1;86(1):28–37. [PubMed] [Google Scholar]
  30. Otsuki T., Yano T., Clark H. M., Bastard C., Kerckaert J. P., Jaffe E. S., Raffeld M. Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin's lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. Blood. 1995 May 15;85(10):2877–2884. [PubMed] [Google Scholar]
  31. Pengue G., Calabrò V., Bartoli P. C., Pagliuca A., Lania L. Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins. Nucleic Acids Res. 1994 Aug 11;22(15):2908–2914. doi: 10.1093/nar/22.15.2908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wright W. E., Binder M., Funk W. Cyclic amplification and selection of targets (CASTing) for the myogenin consensus binding site. Mol Cell Biol. 1991 Aug;11(8):4104–4110. doi: 10.1128/mcb.11.8.4104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Xue F., Cooley L. kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell. 1993 Mar 12;72(5):681–693. doi: 10.1016/0092-8674(93)90397-9. [DOI] [PubMed] [Google Scholar]
  34. Ye B. H., Chaganti S., Chang C. C., Niu H., Corradini P., Chaganti R. S., Dalla-Favera R. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 1995 Dec 15;14(24):6209–6217. doi: 10.1002/j.1460-2075.1995.tb00311.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ye B. H., Lista F., Lo Coco F., Knowles D. M., Offit K., Chaganti R. S., Dalla-Favera R. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993 Oct 29;262(5134):747–750. doi: 10.1126/science.8235596. [DOI] [PubMed] [Google Scholar]
  36. Ye B. H., Rao P. H., Chaganti R. S., Dalla-Favera R. Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res. 1993 Jun 15;53(12):2732–2735. [PubMed] [Google Scholar]
  37. Zollman S., Godt D., Privé G. G., Couderc J. L., Laski F. A. The BTB domain, found primarily in zinc finger proteins, defines an evolutionarily conserved family that includes several developmentally regulated genes in Drosophila. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10717–10721. doi: 10.1073/pnas.91.22.10717. [DOI] [PMC free article] [PubMed] [Google Scholar]

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