Home LiteratureArticle Details
PMID: 7813434 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Transformation by homeobox genes can be mediated by selective transcriptional repression.

The EMBO journal ·Vol. 13 ·No. 24 ·1994-12-15 ·Pages 5967-76

Qin XF, Luo Y, Suh H, Wayne J, Misulovin Z, Roeder RG, Nussenzweig MC

Abstract

Altered transcription is a recurrent theme in the field of cancer biology. But despite the central role of transcription in transformation, little is known about the mechanism by which dominant nuclear oncogenes induce malignancies. Homeobox family proteins are prominent examples of transcriptional regulators which control development and can function as oncogenes. Here we explore the molecular basis for transformation by this class of regulators using Oct-2 and Oct-1. We show that the DNA binding POU domains of these proteins are selective and sequence-specific transcriptional repressors that produce malignant lymphomas when they are expressed in T cells of transgenic mice. Mutagenesis experiments identified a specific set of promoters, those containing octamer regulatory elements, as the targets for transformation by selective inhibition of gene expression.

MeSH Terms
Animals Base Sequence Binding Sites/genetics Cell Transformation, Neoplastic/genetics DNA Mutational Analysis DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation, Neoplastic/genetics Genes, Homeobox/genetics Host Cell Factor C1 Lymphoma, T-Cell/etiology,genetics Mice Mice, Transgenic Molecular Sequence Data Octamer Transcription Factor-1 Octamer Transcription Factor-2 Protein Binding/genetics Regulatory Sequences, Nucleic Acid Transcription Factors/genetics,metabolism Transcription, Genetic
Chemicals
DNA-Binding Proteins Hcfc1 protein, mouse Host Cell Factor C1 Octamer Transcription Factor-1 Octamer Transcription Factor-2 Pou2f1 protein, mouse Pou2f2 protein, mouse Transcription Factors
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Qin X F
Laboratory of Molecular Immunology, Howard Hughes Medical Institute, Rockfeller University.
Luo Y
Suh H
Wayne J
Misulovin Z
Roeder R G
Nussenzweig M C
References (95)
95 references, click to expand
  1. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL.
    Cell. 1990 Feb 23;60(4):547-55 PMID: 1967983
  2. Transcription factor Oct-2A contains functionally redundant activating domains and works selectively from a promoter but not from a remote enhancer position in non-lymphoid (HeLa) cells.
    EMBO J. 1990 May;9(5):1625-34 PMID: 2328728
  3. The cell type-specific octamer transcription factor OTF-2 has two domains required for the activation of transcription.
    EMBO J. 1990 May;9(5):1635-43 PMID: 2328729
  4. The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions.
    Cell. 1990 Jun 15;61(6):1021-33 PMID: 2350782
  5. v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA.
    Cell. 1990 Jun 15;61(6):1035-49 PMID: 1972036
  6. Use of T7 RNA polymerase to direct expression of cloned genes.
    Methods Enzymol. 1990;185:60-89 PMID: 2199796
  7. Structure and expression of the mouse Oct2a and Oct2b, two differentially spliced products of the same gene.
    Development. 1990 Jun;109(2):349-62 PMID: 1976089
  8. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer.
    Genes Dev. 1990 Oct;4(10):1730-40 PMID: 2249772
  9. Molecular themes in oncogenesis.
    Cell. 1991 Jan 25;64(2):235-48 PMID: 1988146
  10. Cooperation between oncogenes.
    Cell. 1991 Jan 25;64(2):249-70 PMID: 1988147
  11. Oncogenic conversion by regulatory changes in transcription factors.
    Cell. 1991 Jan 25;64(2):303-12 PMID: 1988149
  12. Tumor suppressor genes.
    Cell. 1991 Jan 25;64(2):313-26 PMID: 1988150
  13. The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials.
    Genes Dev. 1991 Mar;5(3):358-68 PMID: 1672117
  14. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc.
    Science. 1991 Mar 8;251(4998):1211-7 PMID: 2006410
  15. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen.
    Int Immunol. 1990;2(2):173-80 PMID: 1965144
  16. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation.
    Cell. 1991 May 3;65(3):395-407 PMID: 1840505
  17. Optimal DNA sequence recognition by the Ultrabithorax homeodomain of Drosophila.
    EMBO J. 1991 May;10(5):1179-86 PMID: 1673656
  18. POU-domain transcription factors: pou-er-ful developmental regulators.
    Genes Dev. 1991 Jun;5(6):897-907 PMID: 2044958
  19. Identification of p53 as a sequence-specific DNA-binding protein.
    Science. 1991 Jun 21;252(5013):1708-11 PMID: 2047879
  20. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia.
    Science. 1991 Jul 5;253(5015):79-82 PMID: 1676542
  21. Oncogenic conversion of transcription factors by chromosomal translocations.
    Cell. 1991 Aug 23;66(4):619-22 PMID: 1878967
  22. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
    Cell. 1991 Aug 23;66(4):663-74 PMID: 1652368
  23. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
    Cell. 1991 Aug 23;66(4):675-84 PMID: 1652369
  24. v-erbA oncogene function in neoplasia correlates with its ability to repress retinoic acid receptor action.
    Cell. 1991 Sep 6;66(5):885-93 PMID: 1679679
  25. The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein.
    EMBO J. 1991 Oct;10(10):2905-10 PMID: 1717256
  26. Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max.
    Nature. 1992 Oct 1;359(6394):423-6 PMID: 1406955
  27. Myc and Max proteins possess distinct transcriptional activities.
    Nature. 1992 Oct 1;359(6394):426-9 PMID: 1406956
  28. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors.
    Cell. 1992 Oct 16;71(2):231-41 PMID: 1423591
  29. The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function.
    Cell. 1990 Nov 16;63(4):803-14 PMID: 2225078
  30. Activation of octamer-containing promoters by either octamer-binding transcription factor 1 (OTF-1) or OTF-2 and requirement of an additional B-cell-specific component for optimal transcription of immunoglobulin promoters.
    Mol Cell Biol. 1990 Dec;10(12):6204-15 PMID: 2123291
  31. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase.
    EMBO J. 1990 Dec;9(12):3821-9 PMID: 2123451
  32. POU proteins bend DNA via the POU-specific domain.
    EMBO J. 1991 Oct;10(10):3007-14 PMID: 1915275
  33. HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.
    Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8900-4 PMID: 1681546
  34. Translocations, master genes, and differences between the origins of acute and chronic leukemias.
    Cell. 1991 Nov 15;67(4):641-4 PMID: 1934065
  35. A novel mechanism of action for v-ErbA: abrogation of the inactivation of transcription factor AP-1 by retinoic acid and thyroid hormone receptors.
    Cell. 1991 Nov 15;67(4):731-40 PMID: 1682056
  36. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.
    Mol Cell Biol. 1991 Dec;11(12):6149-57 PMID: 1682799
  37. Purification of his-tagged proteins in non-denaturing conditions suggests a convenient method for protein interaction studies.
    Nucleic Acids Res. 1991 Nov 25;19(22):6337-8 PMID: 1956801
  38. Tumor suppressor genes.
    Science. 1991 Nov 22;254(5035):1138-46 PMID: 1659741
  39. Transgenic models of tumor development.
    Science. 1991 Nov 22;254(5035):1161-7 PMID: 1957168
  40. Homeobox genes and axial patterning.
    Cell. 1992 Jan 24;68(2):283-302 PMID: 1346368
  41. Octamania: the POU factors in murine development.
    Trends Genet. 1991 Oct;7(10):323-9 PMID: 1781030
  42. Recognition of the surface of a homeo domain protein.
    Genes Dev. 1992 Nov;6(11):2047-57 PMID: 1358755
  43. A single amino acid exchange transfers VP16-induced positive control from the Oct-1 to the Oct-2 homeo domain.
    Genes Dev. 1992 Nov;6(11):2058-65 PMID: 1358756
  44. Differential positive control by Oct-1 and Oct-2: activation of a transcriptionally silent motif through Oct-1 and VP16 corecruitment.
    Genes Dev. 1993 Jan;7(1):72-83 PMID: 8422989
  45. Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity.
    Cell. 1993 Jan 29;72(2):211-22 PMID: 8425218
  46. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites.
    Cell. 1993 Jan 29;72(2):223-32 PMID: 8425219
  47. The solution structure of the Oct-1 POU-specific domain reveals a striking similarity to the bacteriophage lambda repressor DNA-binding domain.
    Cell. 1993 Apr 9;73(1):193-205 PMID: 8462099
  48. Solution structure of the POU-specific DNA-binding domain of Oct-1.
    Nature. 1993 Apr 29;362(6423):852-5 PMID: 8479524
  49. POU domain transcription factors.
    Biochim Biophys Acta. 1993 Apr 29;1173(1):1-21 PMID: 8485147
  50. The oncogenic potential of Pax genes.
    EMBO J. 1993 Jun;12(6):2361-7 PMID: 8099544
  51. The multistep nature of cancer.
    Trends Genet. 1993 Apr;9(4):138-41 PMID: 8516849
  52. Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice.
    Cell. 1993 Sep 10;74(5):833-43 PMID: 8104101
  53. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
    Cell. 1993 Nov 19;75(4):805-16 PMID: 8242751
  54. WAF1, a potential mediator of p53 tumor suppression.
    Cell. 1993 Nov 19;75(4):817-25 PMID: 8242752
  55. p21 is a universal inhibitor of cyclin kinases.
    Nature. 1993 Dec 16;366(6456):701-4 PMID: 8259214
  56. A novel cis element mediating ligand-independent activation by c-ErbA: implications for hormonal regulation.
    Cell. 1993 Dec 17;75(6):1095-105 PMID: 7903219
  57. Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules.
    Cell. 1994 Apr 8;77(1):21-32 PMID: 8156594
  58. Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias.
    Oncogene. 1994 Jun;9(6):1641-7 PMID: 8183558
  59. Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation.
    Mol Cell Biol. 1994 Jun;14(6):3938-48 PMID: 7910944
  60. Herpes simplex virus regulatory elements and the immunoglobulin octamer domain bind a common factor and are both targets for virion transactivation.
    Cell. 1988 Feb 12;52(3):435-45 PMID: 2830987
  61. Cloning of a lymphoid-specific cDNA encoding a protein binding the regulatory octamer DNA motif.
    Science. 1988 Jul 29;241(4865):577-80 PMID: 3399892
  62. Transgenic mice bearing the human c-myc gene activated by an immunoglobulin enhancer: a pre-B-cell lymphoma model.
    Proc Natl Acad Sci U S A. 1988 Aug;85(16):6047-51 PMID: 3261863
  63. Mini-Oct and Oct-2c: two novel, functionally diverse murine Oct-2 gene products are differentially expressed in the CNS.
    Neuron. 1992 Mar;8(3):541-58 PMID: 1550677
  64. Oct-1 and Oct-2 potentiate functional interactions of a transcription factor with the proximal sequence element of small nuclear RNA genes.
    Mol Cell Biol. 1992 Jul;12(7):3247-61 PMID: 1535687
  65. Transcription factors: structural families and principles of DNA recognition.
    Annu Rev Biochem. 1992;61:1053-95 PMID: 1497306
  66. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter.
    Nucleic Acids Res. 1984 Sep 25;12(18):7035-56 PMID: 6091052
  67. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes.
    Cell. 1984 Oct;38(3):627-37 PMID: 6488314
  68. Rapid and efficient site-specific mutagenesis without phenotypic selection.
    Proc Natl Acad Sci U S A. 1985 Jan;82(2):488-92 PMID: 3881765
  69. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice.
    Nature. 1985 Dec 12-18;318(6046):533-8 PMID: 3906410
  70. Germ-line transformation of mice.
    Annu Rev Genet. 1986;20:465-99 PMID: 3545063
  71. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu.
    Science. 1987 May 15;236(4803):816-9 PMID: 3107126
  72. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain.
    Cell. 1987 Dec 24;51(6):1079-90 PMID: 3319186
  73. A herpesvirus trans-activating protein interacts with transcription factor OTF-1 and other cellular proteins.
    Proc Natl Acad Sci U S A. 1988 Sep;85(17):6347-51 PMID: 2842768
  74. Isotypic exclusion of gamma delta T cell receptors in transgenic mice bearing a rearranged beta-chain gene.
    Science. 1988 Aug 26;241(4869):1089-92 PMID: 2970670
  75. The sequence specificity of homeodomain-DNA interaction.
    Cell. 1988 Sep 23;54(7):1081-90 PMID: 3046753
  76. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase.
    Gene. 1988 Jul 15;67(1):31-40 PMID: 3047011
  77. A human protein specific for the immunoglobulin octamer DNA motif contains a functional homeobox domain.
    Cell. 1988 Oct 7;55(1):135-44 PMID: 2901913
  78. Homeobox proteins as sequence-specific transcription factors.
    Cell. 1988 Nov 18;55(4):537-40 PMID: 2902929
  79. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells.
    Nature. 1988 Dec 8;336(6199):544-51 PMID: 2904653
  80. A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein.
    Nature. 1988 Dec 8;336(6199):551-7 PMID: 2904654
  81. The POU domain is a bipartite DNA-binding structure.
    Nature. 1988 Dec 8;336(6199):601-4 PMID: 2904656
  82. Octamer-binding proteins from B or HeLa cells stimulate transcription of the immunoglobulin heavy-chain promoter in vitro.
    Genes Dev. 1988 Oct;2(10):1227-37 PMID: 3264542
  83. The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products.
    Genes Dev. 1988 Dec;2(12A):1513-6 PMID: 3215510
  84. The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains.
    Genes Dev. 1988 Dec;2(12A):1570-81 PMID: 3265124
  85. The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain.
    Genes Dev. 1988 Dec;2(12A):1582-99 PMID: 2905684
  86. Functional cooperativity between protein molecules bound at two distinct sequence elements of the immunoglobulin heavy-chain promoter.
    Nature. 1989 Feb 9;337(6207):573-6 PMID: 2492641
  87. Expression of Hox-2.4 homeobox gene directed by proviral insertion in a myeloid leukemia.
    Nucleic Acids Res. 1989 Mar 11;17(5):1881-92 PMID: 2564662
  88. Identification of a novel lymphoid specific octamer binding protein (OTF-2B) by proteolytic clipping bandshift assay (PCBA).
    EMBO J. 1988 Dec 20;7(13):4221-9 PMID: 3072196
  89. Direct combinatorial interaction between a herpes simplex virus regulatory protein and a cellular octamer-binding factor mediates specific induction of virus immediate-early gene expression.
    EMBO J. 1988 Dec 20;7(13):4231-8 PMID: 2854058
  90. DNA rearrangement of a homeobox gene in myeloid leukaemic cells.
    EMBO J. 1988 Dec 20;7(13):4283-90 PMID: 2907477
  91. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist.
    Nature. 1989 Jun 22;339(6226):593-7 PMID: 2733791
  92. The structure and function of the homeodomain.
    Biochim Biophys Acta. 1989 Jul 28;989(1):25-48 PMID: 2568852
  93. The Oct-1 homoeodomain directs formation of a multiprotein-DNA complex with the HSV transactivator VP16.
    Nature. 1989 Oct 19;341(6243):624-30 PMID: 2571937
  94. The octamer-binding proteins form multi-protein--DNA complexes with the HSV alpha TIF regulatory protein.
    EMBO J. 1989 Dec 20;8(13):4229-38 PMID: 2556266
  95. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor.
    Cell. 1990 Feb 23;60(4):535-45 PMID: 1967982
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1994-12-15
Pages
5967-76
Language
English
Region
England
NLM ID
8208664
PMCID
PMC395572
Subset
IM
Grants
NIGMS NIH HHS · GM07982 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2