Abstract
The LIM-only protein Lmo2, activated by chromosomal translocations in T-cell leukaemias, is normally expressed in haematopoiesis. It interacts with TAL1 and GATA-1 proteins, but the function of the interaction is unexplained. We now show that in erythroid cells Lmo2 forms a novel DNA-binding complex, with GATA-1, TAL1 and E2A, and the recently identified LIM-binding protein Ldb1/NLI. This oligomeric complex binds to a unique, bipartite DNA motif comprising an E-box, CAGGTG, followed approximately 9 bp downstream by a GATA site. In vivo assembly of the DNA-binding complex requires interaction of all five proteins and establishes a transcriptional transactivating complex. These data demonstrate one function for the LIM-binding protein Ldb1 and establish a function for the LIM-only protein Lmo2 as an obligatory component of an oligomeric, DNA-binding complex which may play a role in haematopoiesis.
Full Text
The Full Text of this article is available as a PDF (763.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Agulnick A. D., Taira M., Breen J. J., Tanaka T., Dawid I. B., Westphal H. Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature. 1996 Nov 21;384(6606):270–272. doi: 10.1038/384270a0. [DOI] [PubMed] [Google Scholar]
- Baer R. TAL1, TAL2 and LYL1: a family of basic helix-loop-helix proteins implicated in T cell acute leukaemia. Semin Cancer Biol. 1993 Dec;4(6):341–347. [PubMed] [Google Scholar]
- Begley C. G., Aplan P. D., Denning S. M., Haynes B. F., Waldmann T. A., Kirsch I. R. The gene SCL is expressed during early hematopoiesis and encodes a differentiation-related DNA-binding motif. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10128–10132. doi: 10.1073/pnas.86.24.10128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boehm T., Foroni L., Kaneko Y., Perutz M. F., Rabbitts T. H. The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4367–4371. doi: 10.1073/pnas.88.10.4367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carroll A. J., Crist W. M., Link M. P., Amylon M. D., Pullen D. J., Ragab A. H., Buchanan G. R., Wimmer R. S., Vietti T. J. The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1990 Sep 15;76(6):1220–1224. [PubMed] [Google Scholar]
- Cheng J. T., Hsu H. L., Hwang L. Y., Baer R. Products of the TAL1 oncogene: basic helix-loop-helix proteins phosphorylated at serine residues. Oncogene. 1993 Mar;8(3):677–683. [PubMed] [Google Scholar]
- Crossley M., Merika M., Orkin S. H. Self-association of the erythroid transcription factor GATA-1 mediated by its zinc finger domains. Mol Cell Biol. 1995 May;15(5):2448–2456. doi: 10.1128/mcb.15.5.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crossley M., Orkin S. H. Phosphorylation of the erythroid transcription factor GATA-1. J Biol Chem. 1994 Jun 17;269(24):16589–16596. [PubMed] [Google Scholar]
- Feuerstein R., Wang X., Song D., Cooke N. E., Liebhaber S. A. The LIM/double zinc-finger motif functions as a protein dimerization domain. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10655–10659. doi: 10.1073/pnas.91.22.10655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Funk W. D., Wright W. E. Cyclic amplification and selection of targets for multicomponent complexes: myogenin interacts with factors recognizing binding sites for basic helix-loop-helix, nuclear factor 1, myocyte-specific enhancer-binding factor 2, and COMP1 factor. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9484–9488. doi: 10.1073/pnas.89.20.9484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu H. L., Cheng J. T., Chen Q., Baer R. Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins. Mol Cell Biol. 1991 Jun;11(6):3037–3042. doi: 10.1128/mcb.11.6.3037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu H. L., Huang L., Tsan J. T., Funk W., Wright W. E., Hu J. S., Kingston R. E., Baer R. Preferred sequences for DNA recognition by the TAL1 helix-loop-helix proteins. Mol Cell Biol. 1994 Feb;14(2):1256–1265. doi: 10.1128/mcb.14.2.1256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu H. L., Wadman I., Baer R. Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3181–3185. doi: 10.1073/pnas.91.8.3181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jurata L. W., Kenny D. A., Gill G. N. Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11693–11698. doi: 10.1073/pnas.93.21.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karlsson O., Thor S., Norberg T., Ohlsson H., Edlund T. Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain. Nature. 1990 Apr 26;344(6269):879–882. doi: 10.1038/344879a0. [DOI] [PubMed] [Google Scholar]
- Larson R. C., Lavenir I., Larson T. A., Baer R., Warren A. J., Wadman I., Nottage K., Rabbitts T. H. Protein dimerization between Lmo2 (Rbtn2) and Tal1 alters thymocyte development and potentiates T cell tumorigenesis in transgenic mice. EMBO J. 1996 Mar 1;15(5):1021–1027. [PMC free article] [PubMed] [Google Scholar]
- Lee K. A., Bindereif A., Green M. R. A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Anal Tech. 1988 Mar-Apr;5(2):22–31. doi: 10.1016/0735-0651(88)90023-4. [DOI] [PubMed] [Google Scholar]
- Pevny L., Simon M. C., Robertson E., Klein W. H., Tsai S. F., D'Agati V., Orkin S. H., Costantini F. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature. 1991 Jan 17;349(6306):257–260. doi: 10.1038/349257a0. [DOI] [PubMed] [Google Scholar]
- Porcher C., Swat W., Rockwell K., Fujiwara Y., Alt F. W., Orkin S. H. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell. 1996 Jul 12;86(1):47–57. doi: 10.1016/s0092-8674(00)80076-8. [DOI] [PubMed] [Google Scholar]
- Rabbitts T. H. Chromosomal translocations in human cancer. Nature. 1994 Nov 10;372(6502):143–149. doi: 10.1038/372143a0. [DOI] [PubMed] [Google Scholar]
- Robb L., Elwood N. J., Elefanty A. G., Köntgen F., Li R., Barnett L. D., Begley C. G. The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. EMBO J. 1996 Aug 15;15(16):4123–4129. [PMC free article] [PubMed] [Google Scholar]
- Robb L., Lyons I., Li R., Hartley L., Köntgen F., Harvey R. P., Metcalf D., Begley C. G. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7075–7079. doi: 10.1073/pnas.92.15.7075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Royer-Pokora B., Loos U., Ludwig W. D. TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene. 1991 Oct;6(10):1887–1893. [PubMed] [Google Scholar]
- Schmeichel K. L., Beckerle M. C. The LIM domain is a modular protein-binding interface. Cell. 1994 Oct 21;79(2):211–219. doi: 10.1016/0092-8674(94)90191-0. [DOI] [PubMed] [Google Scholar]
- Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995 Feb 2;373(6513):432–434. doi: 10.1038/373432a0. [DOI] [PubMed] [Google Scholar]
- Sánchez-García I., Rabbitts T. H. LIM domain proteins in leukaemia and development. Semin Cancer Biol. 1993 Dec;4(6):349–358. [PubMed] [Google Scholar]
- Tsai F. Y., Keller G., Kuo F. C., Weiss M., Chen J., Rosenblatt M., Alt F. W., Orkin S. H. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994 Sep 15;371(6494):221–226. doi: 10.1038/371221a0. [DOI] [PubMed] [Google Scholar]
- Tsai S. F., Martin D. I., Zon L. I., D'Andrea A. D., Wong G. G., Orkin S. H. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature. 1989 Jun 8;339(6224):446–451. doi: 10.1038/339446a0. [DOI] [PubMed] [Google Scholar]
- Valge-Archer V. E., Osada H., Warren A. J., Forster A., Li J., Baer R., Rabbitts T. H. The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8617–8621. doi: 10.1073/pnas.91.18.8617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss M. J., Keller G., Orkin S. H. Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. Genes Dev. 1994 May 15;8(10):1184–1197. doi: 10.1101/gad.8.10.1184. [DOI] [PubMed] [Google Scholar]
- Weiss M. J., Orkin S. H. GATA transcription factors: key regulators of hematopoiesis. Exp Hematol. 1995 Feb;23(2):99–107. [PubMed] [Google Scholar]
- 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]
- Wright W. E., Funk W. D. CASTing for multicomponent DNA-binding complexes. Trends Biochem Sci. 1993 Mar;18(3):77–80. doi: 10.1016/0968-0004(93)90156-h. [DOI] [PubMed] [Google Scholar]
- Yang H. Y., Evans T. Homotypic interactions of chicken GATA-1 can mediate transcriptional activation. Mol Cell Biol. 1995 Mar;15(3):1353–1363. doi: 10.1128/mcb.15.3.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]