Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1990 May;64(5):2226–2235. doi: 10.1128/jvi.64.5.2226-2235.1990

Conservation of function of Drosophila melanogaster abl and murine v-abl proteins in transformation of mammalian cells.

G D Holland 1, M J Henkemeyer 1, D A Kaehler 1, F M Hoffmann 1, R Risser 1
PMCID: PMC249383  PMID: 2157882

Abstract

The Drosophila melanogaster abl and the murine v-abl genes encode tyrosine protein kinases (TPKs) whose amino acid sequences are highly conserved. To assess functional conservation between the two gene products, we constructed Drosophila abl/v-abl-chimeric Abelson murine leukemia viruses. In these chimeric Abelson murine leukemia viruses, the TPK and carboxy-terminal regions of v-abl were replaced with the corresponding regions of D. melanogaster abl. The chimeric Abelson murine leukemia viruses were able to mediate morphological and oncogenic transformation of NIH 3T3 cells and were able to abrogate the interleukin-3 dependence of a lymphoid cell line. We also found that a virus that contained both TPK and carboxy-terminal Drosophila abl regions had no in vitro transforming activity for primary bone marrow cells and lacked the ability to induce tumors in susceptible mice. A virus that replaced only a portion of the v-abl TPK region with that of Drosophila abl had low activity in in vitro bone marrow transformation and tumorigenesis assays. These results indicate that the transforming functions of abl TPKs are only partially conserved through evolution. These results also imply that the TPK region of v-abl is a major determinant of its efficient lymphoid cell-transforming activity.

Full text

PDF
2226

Images in this article

Selected References

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

  1. Abelson H. T., Rabstein L. S. Influence of prednisolone on Moloney leukemogenic virus in BALB-c mice. Cancer Res. 1970 Aug;30(8):2208–2212. [PubMed] [Google Scholar]
  2. Abelson H. T., Rabstein L. S. Lymphosarcoma: virus-induced thymic-independent disease in mice. Cancer Res. 1970 Aug;30(8):2213–2222. [PubMed] [Google Scholar]
  3. Ben-Neriah Y., Bernards A., Paskind M., Daley G. Q., Baltimore D. Alternative 5' exons in c-abl mRNA. Cell. 1986 Feb 28;44(4):577–586. doi: 10.1016/0092-8674(86)90267-9. [DOI] [PubMed] [Google Scholar]
  4. Bergold P. J., Blumenthal J. A., D'Andrea E., Snyder H. W., Lederman L., Silverstone A., Nguyen H., Besmer P. Nucleic acid sequence and oncogenic properties of the HZ2 feline sarcoma virus v-abl insert. J Virol. 1987 Apr;61(4):1193–1202. doi: 10.1128/jvi.61.4.1193-1202.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bergold P. J., Wang J. Y., Hardy W. D., Jr, Littau V., Johnson E., Besmer P. Structure and origins of the HZ2-feline sarcoma virus. Virology. 1987 Jun;158(2):320–329. doi: 10.1016/0042-6822(87)90204-2. [DOI] [PubMed] [Google Scholar]
  6. Besmer P., Hardy W. D., Jr, Zuckerman E. E., Bergold P., Lederman L., Snyder H. W., Jr The Hardy-Zuckerman 2-FeSV, a new feline retrovirus with oncogene homology to Abelson-MuLV. Nature. 1983 Jun 30;303(5920):825–828. doi: 10.1038/303825a0. [DOI] [PubMed] [Google Scholar]
  7. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  8. Cook W. D., Metcalf D., Nicola N. A., Burgess A. W., Walker F. Malignant transformation of a growth factor-dependent myeloid cell line by Abelson virus without evidence of an autocrine mechanism. Cell. 1985 Jul;41(3):677–683. doi: 10.1016/s0092-8674(85)80048-9. [DOI] [PubMed] [Google Scholar]
  9. DeClue J. E., Sadowski I., Martin G. S., Pawson T. A conserved domain regulates interactions of the v-fps protein-tyrosine kinase with the host cell. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9064–9068. doi: 10.1073/pnas.84.24.9064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  11. Franz W. M., Berger P., Wang J. Y. Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential. EMBO J. 1989 Jan;8(1):137–147. doi: 10.1002/j.1460-2075.1989.tb03358.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gertler F. B., Bennett R. L., Clark M. J., Hoffmann F. M. Drosophila abl tyrosine kinase in embryonic CNS axons: a role in axonogenesis is revealed through dosage-sensitive interactions with disabled. Cell. 1989 Jul 14;58(1):103–113. doi: 10.1016/0092-8674(89)90407-8. [DOI] [PubMed] [Google Scholar]
  13. Goff S. P., Gilboa E., Witte O. N., Baltimore D. Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: studies with cloned viral DNA. Cell. 1980 Dec;22(3):777–785. doi: 10.1016/0092-8674(80)90554-1. [DOI] [PubMed] [Google Scholar]
  14. Green P. L., Kaehler D. A., McKearn J., Risser R. Substitution of the LTR of Abelson murine leukemia virus does not alter the cell type of virally induced tumors. Oncogene. 1988 Jun;2(6):585–592. [PubMed] [Google Scholar]
  15. Green P. L., Kaehler D. A., Risser R. Cell transformation and tumor induction by Abelson murine leukemia virus in the absence of helper virus. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5932–5936. doi: 10.1073/pnas.84.16.5932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Green P. L., Kaehler D. A., Risser R. Clonal dominance and progression in Abelson murine leukemia virus lymphomagenesis. J Virol. 1987 Jul;61(7):2192–2197. doi: 10.1128/jvi.61.7.2192-2197.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Groffen J., Stephenson J. R., Heisterkamp N., de Klein A., Bartram C. R., Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984 Jan;36(1):93–99. doi: 10.1016/0092-8674(84)90077-1. [DOI] [PubMed] [Google Scholar]
  18. Harbers K., Schnieke A., Stuhlmann H., Jähner D., Jaenisch R. DNA methylation and gene expression: endogenous retroviral genome becomes infectious after molecular cloning. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7609–7613. doi: 10.1073/pnas.78.12.7609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heisterkamp N., Stephenson J. R., Groffen J., Hansen P. F., de Klein A., Bartram C. R., Grosveld G. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983 Nov 17;306(5940):239–242. doi: 10.1038/306239a0. [DOI] [PubMed] [Google Scholar]
  20. Henkemeyer M. J., Bennett R. L., Gertler F. B., Hoffmann F. M. DNA sequence, structure, and tyrosine kinase activity of the Drosophila melanogaster Abelson proto-oncogene homolog. Mol Cell Biol. 1988 Feb;8(2):843–853. doi: 10.1128/mcb.8.2.843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Henkemeyer M. J., Gertler F. B., Goodman W., Hoffmann F. M. The Drosophila Abelson proto-oncogene homolog: identification of mutant alleles that have pleiotropic effects late in development. Cell. 1987 Dec 4;51(5):821–828. doi: 10.1016/0092-8674(87)90105-x. [DOI] [PubMed] [Google Scholar]
  22. Hermans A., Heisterkamp N., von Linden M., van Baal S., Meijer D., van der Plas D., Wiedemann L. M., Groffen J., Bootsma D., Grosveld G. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell. 1987 Oct 9;51(1):33–40. doi: 10.1016/0092-8674(87)90007-9. [DOI] [PubMed] [Google Scholar]
  23. Hoffmann F. M., Fresco L. D., Hoffman-Falk H., Shilo B. Z. Nucleotide sequences of the Drosophila src and abl homologs: conservation and variability in the src family oncogenes. Cell. 1983 Dec;35(2 Pt 1):393–401. doi: 10.1016/0092-8674(83)90172-1. [DOI] [PubMed] [Google Scholar]
  24. Ihle J. N., Keller J., Oroszlan S., Henderson L. E., Copeland T. D., Fitch F., Prystowsky M. B., Goldwasser E., Schrader J. W., Palaszynski E. Biologic properties of homogeneous interleukin 3. I. Demonstration of WEHI-3 growth factor activity, mast cell growth factor activity, p cell-stimulating factor activity, colony-stimulating factor activity, and histamine-producing cell-stimulating factor activity. J Immunol. 1983 Jul;131(1):282–287. [PubMed] [Google Scholar]
  25. Jackson P., Baltimore D. N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. EMBO J. 1989 Feb;8(2):449–456. doi: 10.1002/j.1460-2075.1989.tb03397.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jainchill J. L., Aaronson S. A., Todaro G. J. Murine sarcoma and leukemia viruses: assay using clonal lines of contact-inhibited mouse cells. J Virol. 1969 Nov;4(5):549–553. doi: 10.1128/jvi.4.5.549-553.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kamps M. P., Taylor S. S., Sefton B. M. Direct evidence that oncogenic tyrosine kinases and cyclic AMP-dependent protein kinase have homologous ATP-binding sites. Nature. 1984 Aug 16;310(5978):589–592. doi: 10.1038/310589a0. [DOI] [PubMed] [Google Scholar]
  28. Kessler S. W. Rapid isolation of antigens from cells with a staphylococcal protein A-antibody adsorbent: parameters of the interaction of antibody-antigen complexes with protein A. J Immunol. 1975 Dec;115(6):1617–1624. [PubMed] [Google Scholar]
  29. Kloetzer W., Kurzrock R., Smith L., Talpaz M., Spiller M., Gutterman J., Arlinghaus R. The human cellular abl gene product in the chronic myelogenous leukemia cell line K562 has an associated tyrosine protein kinase activity. Virology. 1985 Jan 30;140(2):230–238. doi: 10.1016/0042-6822(85)90361-7. [DOI] [PubMed] [Google Scholar]
  30. Konopka J. B., Witte O. N. Activation of the abl oncogene in murine and human leukemias. Biochim Biophys Acta. 1985 Nov 12;823(1):1–17. doi: 10.1016/0304-419x(85)90012-5. [DOI] [PubMed] [Google Scholar]
  31. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  32. Mathey-Prevot B., Baltimore D. Recombinants within the tyrosine kinase region of v-abl and v-src identify a v-abl segment that confers lymphoid specificity. Mol Cell Biol. 1988 Jan;8(1):234–240. doi: 10.1128/mcb.8.1.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mathey-Prevot B., Hanafusa H., Kawai S. A cellular protein is immunologically crossreactive with and functionally homologous to the Fujinami sarcoma virus transforming protein. Cell. 1982 Apr;28(4):897–906. doi: 10.1016/0092-8674(82)90069-1. [DOI] [PubMed] [Google Scholar]
  34. Mayer B. J., Hamaguchi M., Hanafusa H. A novel viral oncogene with structural similarity to phospholipase C. Nature. 1988 Mar 17;332(6161):272–275. doi: 10.1038/332272a0. [DOI] [PubMed] [Google Scholar]
  35. McCubrey J., Holland G., McKearn J., Risser R. Abrogation of factor-dependence in two IL-3-dependent cell lines can occur by two distinct mechanisms. Oncogene Res. 1989;4(2):97–109. [PubMed] [Google Scholar]
  36. McKearn J. P., McCubrey J., Fagg B. Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7414–7418. doi: 10.1073/pnas.82.21.7414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Oliff A., Agranovsky O., McKinney M. D., Murty V. V., Bauchwitz R. Friend murine leukemia virus-immortalized myeloid cells are converted into tumorigenic cell lines by Abelson leukemia virus. Proc Natl Acad Sci U S A. 1985 May;82(10):3306–3310. doi: 10.1073/pnas.82.10.3306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pierce J. H., Di Fiore P. P., Aaronson S. A., Potter M., Pumphrey J., Scott A., Ihle J. N. Neoplastic transformation of mast cells by Abelson-MuLV: abrogation of IL-3 dependence by a nonautocrine mechanism. Cell. 1985 Jul;41(3):685–693. doi: 10.1016/s0092-8674(85)80049-0. [DOI] [PubMed] [Google Scholar]
  39. Premkumar E., Potter M., Singer P. A., Sklar M. D. Synthesis, surface deposition, and secretion of immunoglobulins by Abelson virus-transformed lymphosarcoma cell lines. Cell. 1975 Oct;6(2):149–159. doi: 10.1016/0092-8674(75)90005-7. [DOI] [PubMed] [Google Scholar]
  40. Prywes R., Foulkes J. G., Baltimore D. The minimum transforming region of v-abl is the segment encoding protein-tyrosine kinase. J Virol. 1985 Apr;54(1):114–122. doi: 10.1128/jvi.54.1.114-122.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Prywes R., Foulkes J. G., Rosenberg N., Baltimore D. Sequences of the A-MuLV protein needed for fibroblast and lymphoid cell transformation. Cell. 1983 Sep;34(2):569–579. doi: 10.1016/0092-8674(83)90389-6. [DOI] [PubMed] [Google Scholar]
  42. Reddy E. P., Smith M. J., Srinivasan A. Nucleotide sequence of Abelson murine leukemia virus genome: structural similarity of its transforming gene product to other onc gene products with tyrosine-specific kinase activity. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3623–3627. doi: 10.1073/pnas.80.12.3623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Risser R., Potter M., Rowe W. P. Abelson virus-induced lymphomagenesis in mice. J Exp Med. 1978 Sep 1;148(3):714–726. doi: 10.1084/jem.148.3.714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Risser R. The pathogenesis of Abelson virus lymphomas of the mouse. Biochim Biophys Acta. 1982 Jun 28;651(4):213–244. doi: 10.1016/0304-419x(82)90013-0. [DOI] [PubMed] [Google Scholar]
  45. Rosenberg N. E., Clark D. R., Witte O. N. Abelson murine leukemia virus mutants deficient in kinase activity and lymphoid cell transformation. J Virol. 1980 Dec;36(3):766–774. doi: 10.1128/jvi.36.3.766-774.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rosenberg N., Baltimore D. A quantitative assay for transformation of bone marrow cells by Abelson murine leukemia virus. J Exp Med. 1976 Jun 1;143(6):1453–1463. doi: 10.1084/jem.143.6.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rosenberg N., Baltimore D., Scher C. D. In vitro transformation of lymphoid cells by Abelson murine leukemia virus. Proc Natl Acad Sci U S A. 1975 May;72(5):1932–1936. doi: 10.1073/pnas.72.5.1932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rowe W. P., Pugh W. E., Hartley J. W. Plaque assay techniques for murine leukemia viruses. Virology. 1970 Dec;42(4):1136–1139. doi: 10.1016/0042-6822(70)90362-4. [DOI] [PubMed] [Google Scholar]
  49. Sadowski I., Stone J. C., Pawson T. A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mol Cell Biol. 1986 Dec;6(12):4396–4408. doi: 10.1128/mcb.6.12.4396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schalken J. A., van den Ouweland A. M., Bloemers H. P., van de Ven W. J. Characterization of the feline c-abl proto-oncogene. Biochim Biophys Acta. 1985 Feb 20;824(2):104–112. doi: 10.1016/0167-4781(85)90086-7. [DOI] [PubMed] [Google Scholar]
  51. Scher C. D., Siegler R. Direct transformation of 3T3 cells by Abelson murine leukaemia virus. Nature. 1975 Feb 27;253(5494):729–731. doi: 10.1038/253729a0. [DOI] [PubMed] [Google Scholar]
  52. Sefton B. M., Hunter T., Raschke W. C. Evidence that the Abelson virus protein functions in vivo as a protein kinase that phosphorylates tyrosine. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1552–1556. doi: 10.1073/pnas.78.3.1552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shilo B. Z., Weinberg R. A. DNA sequences homologous to vertebrate oncogenes are conserved in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6789–6792. doi: 10.1073/pnas.78.11.6789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Shinnick T. M., Lerner R. A., Sutcliffe J. G. Nucleotide sequence of Moloney murine leukaemia virus. Nature. 1981 Oct 15;293(5833):543–548. doi: 10.1038/293543a0. [DOI] [PubMed] [Google Scholar]
  55. Shtivelman E., Lifshitz B., Gale R. P., Roe B. A., Canaani E. Alternative splicing of RNAs transcribed from the human abl gene and from the bcr-abl fused gene. Cell. 1986 Oct 24;47(2):277–284. doi: 10.1016/0092-8674(86)90450-2. [DOI] [PubMed] [Google Scholar]
  56. Sklar M. D., Shevach E. M., Green I., Potter M. Transplantation and preliminary characterisation of lymphocyte surface markers of Abelson virus-induced lymphomas. Nature. 1975 Feb 13;253(5492):550–552. doi: 10.1038/253550a0. [DOI] [PubMed] [Google Scholar]
  57. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  58. Srinivasan A., Dunn C. Y., Yuasa Y., Devare S. G., Reddy E. P., Aaronson S. A. Abelson murine leukemia virus: structural requirements for transforming gene function. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5508–5512. doi: 10.1073/pnas.79.18.5508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Stahl M. L., Ferenz C. R., Kelleher K. L., Kriz R. W., Knopf J. L. Sequence similarity of phospholipase C with the non-catalytic region of src. Nature. 1988 Mar 17;332(6161):269–272. doi: 10.1038/332269a0. [DOI] [PubMed] [Google Scholar]
  60. Waneck G. L., Rosenberg N. Abelson leukemia virus induces lymphoid and erythroid colonies in infected fetal cell cultures. Cell. 1981 Oct;26(1 Pt 1):79–89. doi: 10.1016/0092-8674(81)90035-0. [DOI] [PubMed] [Google Scholar]
  61. Wang J. Y., Ledley F., Goff S., Lee R., Groner Y., Baltimore D. The mouse c-abl locus: molecular cloning and characterization. Cell. 1984 Feb;36(2):349–356. doi: 10.1016/0092-8674(84)90228-9. [DOI] [PubMed] [Google Scholar]
  62. Wang J. Y. Negative regulation of c-abl tyrosine kinase by its variable N-terminal amino acids. Oncogene Res. 1988;3(3):293–298. [PubMed] [Google Scholar]
  63. Witte O. N., Goff S., Rosenberg N., Baltimore D. A transformation-defective mutant of Abelson murine leukemia virus lacks protein kinase activity. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4993–4997. doi: 10.1073/pnas.77.8.4993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Witte O. N., Ponticelli A., Gifford A., Baltimore D., Rosenberg N., Elder J. Phosphorylation of the Abelson murine leukemia virus transforming protein. J Virol. 1981 Sep;39(3):870–878. doi: 10.1128/jvi.39.3.870-878.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES