Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Dec;17(12):7317–7327. doi: 10.1128/mcb.17.12.7317

High incidence of T-cell tumors in E2A-null mice and E2A/Id1 double-knockout mice.

W Yan 1, A Z Young 1, V C Soares 1, R Kelley 1, R Benezra 1, Y Zhuang 1
PMCID: PMC232588  PMID: 9372963

Abstract

The basic-helix-loop-helix (bHLH) proteins encoded by the E2A gene are broadly expressed transcription regulators which function through binding to the E-box enhancer sequences. The DNA binding activities of E2A proteins are directly inhibited upon dimerization with the Id1 gene product. It has been shown that disruption of the E2A gene leads to a complete block in B-lymphocyte development and a high frequency of neonatal death. We report here that nearly half of the surviving E2A-null mice develop acute T-cell lymphoma between 3 to 10 months of age. We further show that disruption of the Id1 gene improves the chance of postnatal survival of E2A-null mice, indicating that Id1 is a canonical negative regulator of E2A and that the unbalanced ratio of E2A to Id1 may contribute to the postnatal death of the E2A-null mice. However, the E2A/Id1 double-knockout mice still develop T-cell tumors once they reach the age of 3 months. This result suggests that E2A may be essential for maintaining the homeostasis of T lymphocytes during their constant renewal in adult life.

Full Text

The Full Text of this article is available as a PDF (3.6 MB).

Selected References

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

  1. Bain G., Maandag E. C., Izon D. J., Amsen D., Kruisbeek A. M., Weintraub B. C., Krop I., Schlissel M. S., Feeney A. J., van Roon M. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell. 1994 Dec 2;79(5):885–892. doi: 10.1016/0092-8674(94)90077-9. [DOI] [PubMed] [Google Scholar]
  2. Barone M. V., Pepperkok R., Peverali F. A., Philipson L. Id proteins control growth induction in mammalian cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4985–4988. doi: 10.1073/pnas.91.11.4985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Benezra R. An intermolecular disulfide bond stabilizes E2A homodimers and is required for DNA binding at physiological temperatures. Cell. 1994 Dec 16;79(6):1057–1067. doi: 10.1016/0092-8674(94)90036-1. [DOI] [PubMed] [Google Scholar]
  5. Benezra R., Davis R. L., Lockshon D., Turner D. L., Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990 Apr 6;61(1):49–59. doi: 10.1016/0092-8674(90)90214-y. [DOI] [PubMed] [Google Scholar]
  6. Chen Q., Cheng J. T., Tasi L. H., Schneider N., Buchanan G., Carroll A., Crist W., Ozanne B., Siciliano M. J., Baer R. The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. EMBO J. 1990 Feb;9(2):415–424. doi: 10.1002/j.1460-2075.1990.tb08126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Choi J. K., Shen C. P., Radomska H. S., Eckhardt L. A., Kadesch T. E47 activates the Ig-heavy chain and TdT loci in non-B cells. EMBO J. 1996 Sep 16;15(18):5014–5021. [PMC free article] [PubMed] [Google Scholar]
  8. Christy B. A., Sanders L. K., Lau L. F., Copeland N. G., Jenkins N. A., Nathans D. An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1815–1819. doi: 10.1073/pnas.88.5.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dedera D. A., Waller E. K., LeBrun D. P., Sen-Majumdar A., Stevens M. E., Barsh G. S., Cleary M. L. Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice. Cell. 1993 Sep 10;74(5):833–843. doi: 10.1016/0092-8674(93)90463-z. [DOI] [PubMed] [Google Scholar]
  10. Ellis H. M., Spann D. R., Posakony J. W. extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins. Cell. 1990 Apr 6;61(1):27–38. doi: 10.1016/0092-8674(90)90212-w. [DOI] [PubMed] [Google Scholar]
  11. Hara E., Uzman J. A., Dimri G. P., Nehlin J. O., Testori A., Campisi J. The helix-loop-helix protein Id-1 and a retinoblastoma protein binding mutant of SV40 T antigen synergize to reactivate DNA synthesis in senescent human fibroblasts. Dev Genet. 1996;18(2):161–172. doi: 10.1002/(SICI)1520-6408(1996)18:2<161::AID-DVG9>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  12. Hara E., Yamaguchi T., Nojima H., Ide T., Campisi J., Okayama H., Oda K. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem. 1994 Jan 21;269(3):2139–2145. [PubMed] [Google Scholar]
  13. Henthorn P., Kiledjian M., Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science. 1990 Jan 26;247(4941):467–470. doi: 10.1126/science.2105528. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Hu J. S., Olson E. N., Kingston R. E. HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Mol Cell Biol. 1992 Mar;12(3):1031–1042. doi: 10.1128/mcb.12.3.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Inaba T., Roberts W. M., Shapiro L. H., Jolly K. W., Raimondi S. C., Smith S. D., Look A. T. Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Science. 1992 Jul 24;257(5069):531–534. doi: 10.1126/science.1386162. [DOI] [PubMed] [Google Scholar]
  17. Jan Y. N., Jan L. Y. HLH proteins, fly neurogenesis, and vertebrate myogenesis. Cell. 1993 Dec 3;75(5):827–830. doi: 10.1016/0092-8674(93)90525-u. [DOI] [PubMed] [Google Scholar]
  18. Jen Y., Manova K., Benezra R. Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Dev Dyn. 1996 Nov;207(3):235–252. doi: 10.1002/(SICI)1097-0177(199611)207:3<235::AID-AJA1>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  19. Jen Y., Weintraub H., Benezra R. Overexpression of Id protein inhibits the muscle differentiation program: in vivo association of Id with E2A proteins. Genes Dev. 1992 Aug;6(8):1466–1479. doi: 10.1101/gad.6.8.1466. [DOI] [PubMed] [Google Scholar]
  20. Johnson S. E., Wang X., Hardy S., Taparowsky E. J., Konieczny S. F. Casein kinase II increases the transcriptional activities of MRF4 and MyoD independently of their direct phosphorylation. Mol Cell Biol. 1996 Apr;16(4):1604–1613. doi: 10.1128/mcb.16.4.1604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kamps M. P., Baltimore D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol Cell Biol. 1993 Jan;13(1):351–357. doi: 10.1128/mcb.13.1.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kamps M. P., Murre C., Sun X. H., Baltimore D. 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):547–555. doi: 10.1016/0092-8674(90)90658-2. [DOI] [PubMed] [Google Scholar]
  23. Kelliher M. A., Seldin D. C., Leder P. Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha. EMBO J. 1996 Oct 1;15(19):5160–5166. [PMC free article] [PubMed] [Google Scholar]
  24. Kreider B. L., Benezra R., Rovera G., Kadesch T. Inhibition of myeloid differentiation by the helix-loop-helix protein Id. Science. 1992 Mar 27;255(5052):1700–1702. doi: 10.1126/science.1372755. [DOI] [PubMed] [Google Scholar]
  25. Lassar A. B., Davis R. L., Wright W. E., Kadesch T., Murre C., Voronova A., Baltimore D., Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell. 1991 Jul 26;66(2):305–315. doi: 10.1016/0092-8674(91)90620-e. [DOI] [PubMed] [Google Scholar]
  26. Lister J., Forrester W. C., Baron M. H. Inhibition of an erythroid differentiation switch by the helix-loop-helix protein Id1. J Biol Chem. 1995 Jul 28;270(30):17939–17946. doi: 10.1074/jbc.270.30.17939. [DOI] [PubMed] [Google Scholar]
  27. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  28. Nourse J., Mellentin J. D., Galili N., Wilkinson J., Stanbridge E., Smith S. D., Cleary M. L. 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):535–545. doi: 10.1016/0092-8674(90)90657-z. [DOI] [PubMed] [Google Scholar]
  29. Peverali F. A., Ramqvist T., Saffrich R., Pepperkok R., Barone M. V., Philipson L. Regulation of G1 progression by E2A and Id helix-loop-helix proteins. EMBO J. 1994 Sep 15;13(18):4291–4301. doi: 10.1002/j.1460-2075.1994.tb06749.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pongubala J. M., Atchison M. L. Functional characterization of the developmentally controlled immunoglobulin kappa 3' enhancer: regulation by Id, a repressor of helix-loop-helix transcription factors. Mol Cell Biol. 1991 Feb;11(2):1040–1047. doi: 10.1128/mcb.11.2.1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Riechmann V., van Crüchten I., Sablitzky F. The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic Acids Res. 1994 Mar 11;22(5):749–755. doi: 10.1093/nar/22.5.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Robb L., Begley C. G. The helix-loop-helix gene SCL: implicated in T-cell acute lymphoblastic leukaemia and in normal haematopoietic development. Int J Biochem Cell Biol. 1996 Jun;28(6):609–618. doi: 10.1016/1357-2725(96)00006-4. [DOI] [PubMed] [Google Scholar]
  33. Schlissel M., Voronova A., Baltimore D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev. 1991 Aug;5(8):1367–1376. doi: 10.1101/gad.5.8.1367. [DOI] [PubMed] [Google Scholar]
  34. Shen C. P., Kadesch T. B-cell-specific DNA binding by an E47 homodimer. Mol Cell Biol. 1995 Aug;15(8):4518–4524. doi: 10.1128/mcb.15.8.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Sloan S. R., Shen C. P., McCarrick-Walmsley R., Kadesch T. Phosphorylation of E47 as a potential determinant of B-cell-specific activity. Mol Cell Biol. 1996 Dec;16(12):6900–6908. doi: 10.1128/mcb.16.12.6900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sun X. H. Constitutive expression of the Id1 gene impairs mouse B cell development. Cell. 1994 Dec 2;79(5):893–900. doi: 10.1016/0092-8674(94)90078-7. [DOI] [PubMed] [Google Scholar]
  38. Sun X. H., Copeland N. G., Jenkins N. A., Baltimore D. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol. 1991 Nov;11(11):5603–5611. doi: 10.1128/mcb.11.11.5603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Swiatek P. J., Gridley T. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev. 1993 Nov;7(11):2071–2084. doi: 10.1101/gad.7.11.2071. [DOI] [PubMed] [Google Scholar]
  40. Tournay O., Benezra R. Transcription of the dominant-negative helix-loop-helix protein Id1 is regulated by a protein complex containing the immediate-early response gene Egr-1. Mol Cell Biol. 1996 May;16(5):2418–2430. doi: 10.1128/mcb.16.5.2418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weintraub H. The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell. 1993 Dec 31;75(7):1241–1244. doi: 10.1016/0092-8674(93)90610-3. [DOI] [PubMed] [Google Scholar]
  42. Wilson R. B., Kiledjian M., Shen C. P., Benezra R., Zwollo P., Dymecki S. M., Desiderio S. V., Kadesch T. Repression of immunoglobulin enhancers by the helix-loop-helix protein Id: implications for B-lymphoid-cell development. Mol Cell Biol. 1991 Dec;11(12):6185–6191. doi: 10.1128/mcb.11.12.6185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yoshihara T., Inaba T., Shapiro L. H., Kato J. Y., Look A. T. E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF. Mol Cell Biol. 1995 Jun;15(6):3247–3255. doi: 10.1128/mcb.15.6.3247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zhuang Y., Cheng P., Weintraub H. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol. 1996 Jun;16(6):2898–2905. doi: 10.1128/mcb.16.6.2898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zhuang Y., Soriano P., Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994 Dec 2;79(5):875–884. doi: 10.1016/0092-8674(94)90076-0. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES