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. 1996 May;70(5):3280–3285. doi: 10.1128/jvi.70.5.3280-3285.1996

Repression of the NF1 gene by Tax may expain the development of neurofibromas in human T-lymphotropic virus type 1 transgenic mice.

L Feigenbaum 1, K Fujita 1, F S Collins 1, G Jay 1
PMCID: PMC190194  PMID: 8627811

Abstract

In familial neurofibromatosis type 1 (NF1), individuals with a germ line-transmitted NF1 mutation develop multiple neurofibromas. To explain the observation that transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) tax gene under the control of the viral regulatory element also develop multiple neurofibromas, we demonstrate that the Tax trans-regulator can functionally repress NF1 gene expression through a cis-acting element located immediately upstream of its transcriptional start site, thereby allowing the development of benign neurofibromas without the need for direct mutations in NF1. We propose that such a mechanism would suffice to epigenetically alter NF1 gene expression. The fact that transgenic animals have localized rather than diffuse neurofibroma formation, however, suggests that additional genetic or epigenetic events may be required for neurofibroma formation.

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Selected References

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  1. Adya N., Zhao L. J., Huang W., Boros I., Giam C. Z. Expansion of CREB's DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5642–5646. doi: 10.1073/pnas.91.12.5642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ballester R., Marchuk D., Boguski M., Saulino A., Letcher R., Wigler M., Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851–859. doi: 10.1016/0092-8674(90)90151-4. [DOI] [PubMed] [Google Scholar]
  3. Bieberich C. J., King C. M., Tinkle B. T., Jay G. A transgenic model of transactivation by the Tax protein of HTLV-I. Virology. 1993 Sep;196(1):309–318. doi: 10.1006/viro.1993.1481. [DOI] [PubMed] [Google Scholar]
  4. Bieberich C. J., Utset M. F., Awgulewitsch A., Ruddle F. H. Evidence for positive and negative regulation of the Hox-3.1 gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8462–8466. doi: 10.1073/pnas.87.21.8462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brannan C. I., Perkins A. S., Vogel K. S., Ratner N., Nordlund M. L., Reid S. W., Buchberg A. M., Jenkins N. A., Parada L. F., Copeland N. G. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994 May 1;8(9):1019–1029. doi: 10.1101/gad.8.9.1019. [DOI] [PubMed] [Google Scholar]
  6. Catovsky D., Greaves M. F., Rose M., Galton D. A., Goolden A. W., McCluskey D. R., White J. M., Lampert I., Bourikas G., Ireland R. Adult T-cell lymphoma-leukaemia in Blacks from the West Indies. Lancet. 1982 Mar 20;1(8273):639–643. doi: 10.1016/s0140-6736(82)92200-0. [DOI] [PubMed] [Google Scholar]
  7. Cawthon R. M., Weiss R., Xu G. F., Viskochil D., Culver M., Stevens J., Robertson M., Dunn D., Gesteland R., O'Connell P. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193–201. doi: 10.1016/0092-8674(90)90253-b. [DOI] [PubMed] [Google Scholar]
  8. Daston M. M., Scrable H., Nordlund M., Sturbaum A. K., Nissen L. M., Ratner N. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron. 1992 Mar;8(3):415–428. doi: 10.1016/0896-6273(92)90270-n. [DOI] [PubMed] [Google Scholar]
  9. DeClue J. E., Cohen B. D., Lowy D. R. Identification and characterization of the neurofibromatosis type 1 protein product. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9914–9918. doi: 10.1073/pnas.88.22.9914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fujii M., Tsuchiya H., Chuhjo T., Akizawa T., Seiki M. Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes. Genes Dev. 1992 Nov;6(11):2066–2076. doi: 10.1101/gad.6.11.2066. [DOI] [PubMed] [Google Scholar]
  11. Fukumoto S., Matsumoto T., Ikeda K., Yamashita T., Watanabe T., Yamaguchi K., Kiyokawa T., Takatsuki K., Shibuya N., Ogata E. Clinical evaluation of calcium metabolism in adult T-cell leukemia/lymphoma. Arch Intern Med. 1988 Apr;148(4):921–925. [PubMed] [Google Scholar]
  12. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  13. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Green J. E., Baird A. M., Hinrichs S. H., Klintworth G. K., Jay G. Adrenal medullary tumors and iris proliferation in a transgenic mouse model of neurofibromatosis. Am J Pathol. 1992 Jun;140(6):1401–1410. [PMC free article] [PubMed] [Google Scholar]
  15. Green J. E., Begley C. G., Wagner D. K., Waldmann T. A., Jay G. trans activation of granulocyte-macrophage colony-stimulating factor and the interleukin-2 receptor in transgenic mice carrying the human T-lymphotropic virus type 1 tax gene. Mol Cell Biol. 1989 Nov;9(11):4731–4737. doi: 10.1128/mcb.9.11.4731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Green J. E., Hinrichs S. H., Vogel J., Jay G. Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice. Nature. 1989 Sep 7;341(6237):72–74. doi: 10.1038/341072a0. [DOI] [PubMed] [Google Scholar]
  17. Hajra A., Martin-Gallardo A., Tarlé S. A., Freedman M., Wilson-Gunn S., Bernards A., Collins F. S. DNA sequences in the promoter region of the NF1 gene are highly conserved between human and mouse. Genomics. 1994 Jun;21(3):649–652. doi: 10.1006/geno.1994.1328. [DOI] [PubMed] [Google Scholar]
  18. Herman J. G., Latif F., Weng Y., Lerman M. I., Zbar B., Liu S., Samid D., Duan D. S., Gnarra J. R., Linehan W. M. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700–9704. doi: 10.1073/pnas.91.21.9700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hinrichs S. H., Nerenberg M., Reynolds R. K., Khoury G., Jay G. A transgenic mouse model for human neurofibromatosis. Science. 1987 Sep 11;237(4820):1340–1343. doi: 10.1126/science.2888191. [DOI] [PubMed] [Google Scholar]
  20. Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Imada K., Takaori-Kondo A., Akagi T., Shimotohno K., Sugamura K., Hattori T., Yamabe H., Okuma M., Uchiyama T. Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo. Blood. 1995 Sep 15;86(6):2350–2357. [PubMed] [Google Scholar]
  22. Ishii K., Yamato K., Iwahara Y., Eguchi T., Uemura Y., Takehara N., Ohtsuki Y., Taguchi H., Miyoshi I. Isolation of HTLV-I from muscle of a patient with polymyositis. Am J Med. 1991 Feb;90(2):267–269. [PubMed] [Google Scholar]
  23. Jacks T., Shih T. S., Schmitt E. M., Bronson R. T., Bernards A., Weinberg R. A. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994 Jul;7(3):353–361. doi: 10.1038/ng0794-353. [DOI] [PubMed] [Google Scholar]
  24. LaGrenade L., Hanchard B., Fletcher V., Cranston B., Blattner W. Infective dermatitis of Jamaican children: a marker for HTLV-I infection. Lancet. 1990 Dec 1;336(8727):1345–1347. doi: 10.1016/0140-6736(90)92896-p. [DOI] [PubMed] [Google Scholar]
  25. Martin G. A., Viskochil D., Bollag G., McCabe P. C., Crosier W. J., Haubruck H., Conroy L., Clark R., O'Connell P., Cawthon R. M. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990 Nov 16;63(4):843–849. doi: 10.1016/0092-8674(90)90150-d. [DOI] [PubMed] [Google Scholar]
  26. Mora C. A., Garruto R. M., Brown P., Guiroy D., Morgan O. S., Rodgers-Johnson P., Ceroni M., Yanagihara R., Goldfarb L. G., Gibbs C. J., Jr Seroprevalence of antibodies to HTLV-I in patients with chronic neurological disorders other than tropical spastic paraparesis. Ann Neurol. 1988;23 (Suppl):S192–S195. doi: 10.1002/ana.410230743. [DOI] [PubMed] [Google Scholar]
  27. Nerenberg M., Hinrichs S. H., Reynolds R. K., Khoury G., Jay G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987 Sep 11;237(4820):1324–1329. doi: 10.1126/science.2888190. [DOI] [PubMed] [Google Scholar]
  28. Pavlakis G. N., Felber B. K., Ciminale V., Unge T., Solomin L., Harrison J. E. Structure, regulation and oncogenic mechanisms of HTLV-I and HTLV-II. Leukemia. 1992;6 (Suppl 3):176S–180S. [PubMed] [Google Scholar]
  29. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pollock R. A., Jay G., Bieberich C. J. Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell. 1992 Dec 11;71(6):911–923. doi: 10.1016/0092-8674(92)90388-s. [DOI] [PubMed] [Google Scholar]
  31. Riccardi V. M. Von Recklinghausen neurofibromatosis. N Engl J Med. 1981 Dec 31;305(27):1617–1627. doi: 10.1056/NEJM198112313052704. [DOI] [PubMed] [Google Scholar]
  32. Roberts S. G., Green M. R. Transcription. Dichotomous regulators. Nature. 1995 May 11;375(6527):105–106. doi: 10.1038/375105a0. [DOI] [PubMed] [Google Scholar]
  33. Rodgers-Johnson P., Gajdusek D. C., Morgan O. S., Zaninovic V., Sarin P. S., Graham D. S. HTLV-I and HTLV-III antibodies and tropical spastic paraparesis. Lancet. 1985 Nov 30;2(8466):1247–1248. doi: 10.1016/s0140-6736(85)90778-0. [DOI] [PubMed] [Google Scholar]
  34. Ruddle N. H., Li C. B., Horne W. C., Santiago P., Troiano N., Jay G., Horowitz M., Baron R. Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover. Virology. 1993 Nov;197(1):196–204. doi: 10.1006/viro.1993.1580. [DOI] [PubMed] [Google Scholar]
  35. Scrable H. J., Sapienza C., Cavenee W. K. Genetic and epigenetic losses of heterozygosity in cancer predisposition and progression. Adv Cancer Res. 1990;54:25–62. doi: 10.1016/s0065-230x(08)60807-6. [DOI] [PubMed] [Google Scholar]
  36. Smith F. B., Rajdeo H., Panesar N., Bhuta K., Stahl R. Benign lymphoepithelial lesion of the parotid gland in intravenous drug users. Arch Pathol Lab Med. 1988 Jul;112(7):742–745. [PubMed] [Google Scholar]
  37. Sowa J. M. Human T lymphotropic virus I, myelopathy, polymyositis and synovitis: an expanding rheumatic spectrum. J Rheumatol. 1992 Feb;19(2):316–318. [PubMed] [Google Scholar]
  38. Ueda H., Ullrich S. J., Gangemi J. D., Kappel C. A., Ngo L., Feitelson M. A., Jay G. Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet. 1995 Jan;9(1):41–47. doi: 10.1038/ng0195-41. [DOI] [PubMed] [Google Scholar]
  39. Vernant J. C., Buisson G., Magdeleine J., De Thore J., Jouannelle A., Neisson-Vernant C., Monplaisir N. T-lymphocyte alveolitis, tropical spastic paresis, and Sjögren syndrome. Lancet. 1988 Jan 23;1(8578):177–177. doi: 10.1016/s0140-6736(88)92744-4. [DOI] [PubMed] [Google Scholar]
  40. Viskochil D., Buchberg A. M., Xu G., Cawthon R. M., Stevens J., Wolff R. K., Culver M., Carey J. C., Copeland N. G., Jenkins N. A. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul 13;62(1):187–192. doi: 10.1016/0092-8674(90)90252-a. [DOI] [PubMed] [Google Scholar]
  41. Wagner S., Green M. R. HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science. 1993 Oct 15;262(5132):395–399. doi: 10.1126/science.8211160. [DOI] [PubMed] [Google Scholar]
  42. Wallace M. R., Marchuk D. A., Andersen L. B., Letcher R., Odeh H. M., Saulino A. M., Fountain J. W., Brereton A., Nicholson J., Mitchell A. L. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181–186. doi: 10.1126/science.2134734. [DOI] [PubMed] [Google Scholar]
  43. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
  44. Xu G. F., Lin B., Tanaka K., Dunn D., Wood D., Gesteland R., White R., Weiss R., Tamanoi F. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990 Nov 16;63(4):835–841. doi: 10.1016/0092-8674(90)90149-9. [DOI] [PubMed] [Google Scholar]
  45. Yin M. J., Paulssen E. J., Seeler J. S., Gaynor R. B. Protein domains involved in both in vivo and in vitro interactions between human T-cell leukemia virus type I tax and CREB. J Virol. 1995 Jun;69(6):3420–3432. doi: 10.1128/jvi.69.6.3420-3432.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yoshida M. HTLV-1 Tax: regulation of gene expression and disease. Trends Microbiol. 1993 Jul;1(4):131–135. doi: 10.1016/0966-842x(93)90127-d. [DOI] [PubMed] [Google Scholar]
  47. Yoshioka T., Feigenbaum L., Jay G. Transgenic mouse model for central nervous system demyelination. Mol Cell Biol. 1991 Nov;11(11):5479–5486. doi: 10.1128/mcb.11.11.5479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zhao L. J., Giam C. Z. Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7070–7074. doi: 10.1073/pnas.89.15.7070. [DOI] [PMC free article] [PubMed] [Google Scholar]

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