Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1994 Oct 3;13(19):4515–4523. doi: 10.1002/j.1460-2075.1994.tb06773.x

Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene.

C E Andoniou 1, C B Thien 1, W Y Langdon 1
PMCID: PMC395384  PMID: 7925293

Abstract

v-cbl is the transforming gene of a murine retrovirus which induces pre-B cell lymphomas and myelogenous leukaemias. It encodes 40 kDa of a gag fusion protein which is localized in the cytoplasm and nucleus of infected cells. The c-cbl oncogene encodes a 120 kDa cytoplasmic protein and its overexpression is not associated with tumorigenesis. The c-cbl sequence has shown that v-cbl was generated by a truncation that removed 60% of the C-terminus. In this study, we carried out experiments to identify the position within cbl where the transition occurs between non-tumorigenic and tumorigenic forms. These experiments focused attention on a region of 17 amino acids which is deleted from cbl in the 70Z/3 pre-B lymphoma due to a splice acceptor site mutation. This mutation activates cbl's tumorigenic potential and induces its tyrosine phosphorylation. We also show that the expression of the v-abl and bcr-abl oncogenes results in the induction of cbl tyrosine phosphorylation, and that abl and cbl associate in vivo. These findings demonstrate that tyrosine-phosphorylated cbl promotes tumorigenesis and that cbl is a downstream target of the bcr-abl and v-abl kinases.

Full text

PDF
4515

Images in this article

4517Image
on p.4517
4517Image
on p.4517
4518Image
on p.4518
4519Image
on p.4519
4519Image
on p.4519
4520Image
on p.4520
4520Image
on p.4520
4521Image
on p.4521

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. Lymphosarcoma: virus-induced thymic-independent disease in mice. Cancer Res. 1970 Aug;30(8):2213–2222. [PubMed] [Google Scholar]
  2. Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
  3. Blake T. J., Heath K. G., Langdon W. Y. The truncation that generated the v-cbl oncogene reveals an ability for nuclear transport, DNA binding and acute transformation. EMBO J. 1993 May;12(5):2017–2026. doi: 10.1002/j.1460-2075.1993.tb05851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blake T. J., Langdon W. Y. A rearrangement of the c-cbl proto-oncogene in HUT78 T-lymphoma cells results in a truncated protein. Oncogene. 1992 Apr;7(4):757–762. [PubMed] [Google Scholar]
  5. Blake T. J., Shapiro M., Morse H. C., 3rd, Langdon W. Y. The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif. Oncogene. 1991 Apr;6(4):653–657. [PubMed] [Google Scholar]
  6. Blank V., Kourilsky P., Israël A. Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus. EMBO J. 1991 Dec;10(13):4159–4167. doi: 10.1002/j.1460-2075.1991.tb04994.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281–302. doi: 10.1016/0092-8674(91)90639-g. [DOI] [PubMed] [Google Scholar]
  8. Chelsky D., Ralph R., Jonak G. Sequence requirements for synthetic peptide-mediated translocation to the nucleus. Mol Cell Biol. 1989 Jun;9(6):2487–2492. doi: 10.1128/mcb.9.6.2487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen Y. Y., Wang L. C., Huang M. S., Rosenberg N. An active v-abl protein tyrosine kinase blocks immunoglobulin light-chain gene rearrangement. Genes Dev. 1994 Mar 15;8(6):688–697. doi: 10.1101/gad.8.6.688. [DOI] [PubMed] [Google Scholar]
  10. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  11. Chou M. M., Fajardo J. E., Hanafusa H. The SH2- and SH3-containing Nck protein transforms mammalian fibroblasts in the absence of elevated phosphotyrosine levels. Mol Cell Biol. 1992 Dec;12(12):5834–5842. doi: 10.1128/mcb.12.12.5834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Daley G. Q., Van Etten R. A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. doi: 10.1126/science.2406902. [DOI] [PubMed] [Google Scholar]
  13. Druker B., Okuda K., Matulonis U., Salgia R., Roberts T., Griffin J. D. Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines. Blood. 1992 May 1;79(9):2215–2220. [PubMed] [Google Scholar]
  14. Ellis C., Moran M., McCormick F., Pawson T. Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature. 1990 Jan 25;343(6256):377–381. doi: 10.1038/343377a0. [DOI] [PubMed] [Google Scholar]
  15. FOLEY G. E., LAZARUS H., FARBER S., UZMAN B. G., BOONE B. A., MCCARTHY R. E. CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965 Apr;18:522–529. doi: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Freemont P. S., Hanson I. M., Trowsdale J. A novel cysteine-rich sequence motif. Cell. 1991 Feb 8;64(3):483–484. doi: 10.1016/0092-8674(91)90229-r. [DOI] [PubMed] [Google Scholar]
  18. Ghosh S., Gifford A. M., Riviere L. R., Tempst P., Nolan G. P., Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019–1029. doi: 10.1016/0092-8674(90)90276-k. [DOI] [PubMed] [Google Scholar]
  19. Gishizky M. L., Johnson-White J., Witte O. N. Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3755–3759. doi: 10.1073/pnas.90.8.3755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Hiraki S., Miyoshi I., Masuji H., Kubonishi I., Matsuda Y. Establishment of an Epstein-Barr virus-determined nuclear antigen-negative human B-cell line from acute lymphoblastic leukemia. J Natl Cancer Inst. 1977 Jul;59(1):93–94. doi: 10.1093/jnci/59.1.93. [DOI] [PubMed] [Google Scholar]
  22. Holmes K. L., Pierce J. H., Davidson W. F., Morse H. C., 3rd Murine hematopoietic cells with pre-B or pre-B/myeloid characteristics are generated by in vitro transformation with retroviruses containing fes, ras, abl, and src oncogenes. J Exp Med. 1986 Aug 1;164(2):443–457. doi: 10.1084/jem.164.2.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Johnson G. R., Gonda T. J., Metcalf D., Hariharan I. K., Cory S. A lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulating factor. EMBO J. 1989 Feb;8(2):441–448. doi: 10.1002/j.1460-2075.1989.tb03396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kieran M., Blank V., Logeat F., Vandekerckhove J., Lottspeich F., Le Bail O., Urban M. B., Kourilsky P., Baeuerle P. A., Israël A. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007–1018. doi: 10.1016/0092-8674(90)90275-j. [DOI] [PubMed] [Google Scholar]
  26. Klug C. A., Gerety S. J., Shah P. C., Chen Y. Y., Rice N. R., Rosenberg N., Singh H. The v-abl tyrosine kinase negatively regulates NF-kappa B/Rel factors and blocks kappa gene transcription in pre-B lymphocytes. Genes Dev. 1994 Mar 15;8(6):678–687. doi: 10.1101/gad.8.6.678. [DOI] [PubMed] [Google Scholar]
  27. Koch C. A., Anderson D., Moran M. F., Ellis C., Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668–674. doi: 10.1126/science.1708916. [DOI] [PubMed] [Google Scholar]
  28. Kurzrock R., Gutterman J. U., Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988 Oct 13;319(15):990–998. doi: 10.1056/NEJM198810133191506. [DOI] [PubMed] [Google Scholar]
  29. Langdon W. Y., Hartley J. W., Klinken S. P., Ruscetti S. K., Morse H. C., 3rd v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1168–1172. doi: 10.1073/pnas.86.4.1168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lehmann J. M., Riethmüller G., Johnson J. P. Nck, a melanoma cDNA encoding a cytoplasmic protein consisting of the src homology units SH2 and SH3. Nucleic Acids Res. 1990 Feb 25;18(4):1048–1048. doi: 10.1093/nar/18.4.1048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Li W., Hu P., Skolnik E. Y., Ullrich A., Schlessinger J. The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors. Mol Cell Biol. 1992 Dec;12(12):5824–5833. doi: 10.1128/mcb.12.12.5824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lovering R., Hanson I. M., Borden K. L., Martin S., O'Reilly N. J., Evan G. I., Rahman D., Pappin D. J., Trowsdale J., Freemont P. S. Identification and preliminary characterization of a protein motif related to the zinc finger. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2112–2116. doi: 10.1073/pnas.90.6.2112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lugo T. G., Pendergast A. M., Muller A. J., Witte O. N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990 Mar 2;247(4946):1079–1082. doi: 10.1126/science.2408149. [DOI] [PubMed] [Google Scholar]
  34. Matsuguchi T., Salgia R., Hallek M., Eder M., Druker B., Ernst T. J., Griffin J. D. Shc phosphorylation in myeloid cells is regulated by granulocyte macrophage colony-stimulating factor, interleukin-3, and steel factor and is constitutively increased by p210BCR/ABL. J Biol Chem. 1994 Feb 18;269(7):5016–5021. [PubMed] [Google Scholar]
  35. Muller A. J., Young J. C., Pendergast A. M., Pondel M., Landau N. R., Littman D. R., Witte O. N. BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Mol Cell Biol. 1991 Apr;11(4):1785–1792. doi: 10.1128/mcb.11.4.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Naldini L., Stacchini A., Cirillo D. M., Aglietta M., Gavosto F., Comoglio P. M. Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells. Mol Cell Biol. 1986 May;6(5):1803–1811. doi: 10.1128/mcb.6.5.1803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Paige C. J., Kincade P. W., Ralph P. Murine B cell leukemia line with inducible surface immunoglobulin expression. J Immunol. 1978 Aug;121(2):641–647. [PubMed] [Google Scholar]
  38. Puil L., Liu J., Gish G., Mbamalu G., Bowtell D., Pelicci P. G., Arlinghaus R., Pawson T. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994 Feb 15;13(4):764–773. doi: 10.1002/j.1460-2075.1994.tb06319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ren R., Ye Z. S., Baltimore D. Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev. 1994 Apr 1;8(7):783–795. doi: 10.1101/gad.8.7.783. [DOI] [PubMed] [Google Scholar]
  40. Rivero-Lezcano O. M., Sameshima J. H., Marcilla A., Robbins K. C. Physical association between Src homology 3 elements and the protein product of the c-cbl proto-oncogene. J Biol Chem. 1994 Jul 1;269(26):17363–17366. [PubMed] [Google Scholar]
  41. Rosenberg N., Witte O. N. The viral and cellular forms of the Abelson (abl) oncogene. Adv Virus Res. 1988;35:39–81. doi: 10.1016/s0065-3527(08)60708-3. [DOI] [PubMed] [Google Scholar]
  42. Sawyers C. L., McLaughlin J., Goga A., Havlik M., Witte O. The nuclear tyrosine kinase c-Abl negatively regulates cell growth. Cell. 1994 Apr 8;77(1):121–131. doi: 10.1016/0092-8674(94)90240-2. [DOI] [PubMed] [Google Scholar]
  43. Sawyers C. L. The bcr-abl gene in chronic myelogenous leukaemia. Cancer Surv. 1992;15:37–51. [PubMed] [Google Scholar]
  44. Shi Y., Seto E., Chang L. S., Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. doi: 10.1016/0092-8674(91)90189-6. [DOI] [PubMed] [Google Scholar]
  45. Van Etten R. A., Jackson P., Baltimore D. The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell. 1989 Aug 25;58(4):669–678. doi: 10.1016/0092-8674(89)90102-5. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES