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. 1995 Nov;15(11):6088–6099. doi: 10.1128/mcb.15.11.6088

Nuclear localization of v-Abl leads to complex formation with cyclic AMP response element (CRE)-binding protein and transactivation through CRE motifs.

M C Birchenall-Roberts 1, F W Ruscetti 1, J J Kasper 1, D C Bertolette 3rd 1, Y D Yoo 1, O S Bang 1, M S Roberts 1, J M Turley 1, D K Ferris 1, S J Kim 1
PMCID: PMC230860  PMID: 7565761

Abstract

Deregulated expression of v-abl and BCR/abl genes has been associated with myeloproliferative syndromes and myelodysplasia, both of which can progress to acute leukemia. These studies identify the localization of the oncogenic form of the abl gene product encoded by the Abelson murine leukemia virus in the nuclei of myeloid cells and the association of the v-Abl protein with the transcriptional regulator cyclic AMP response element-binding protein (CREB). We have mapped the specific domains within each of the proteins responsible for this interaction. We have shown that complex formation is a prerequisite for transcriptional potentiation of CREB. Transient overexpression of the homologous cellular protein c-Abl also results in the activation of promoters containing an intact CRE. These observations identify a novel function for v-Abl, that of a transcriptional activator that physically interacts with a transcription factor.

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Selected References

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  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. Arany Z., Sellers W. R., Livingston D. M., Eckner R. E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators. Cell. 1994 Jun 17;77(6):799–800. doi: 10.1016/0092-8674(94)90127-9. [DOI] [PubMed] [Google Scholar]
  3. Baskaran R., Dahmus M. E., Wang J. Y. Tyrosine phosphorylation of mammalian RNA polymerase II carboxyl-terminal domain. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11167–11171. doi: 10.1073/pnas.90.23.11167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birchenall-Roberts M. C., Ruscetti F. W., Kasper J., Lee H. D., Friedman R., Geiser A., Sporn M. B., Roberts A. B., Kim S. J. Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol. 1990 Sep;10(9):4978–4983. doi: 10.1128/mcb.10.9.4978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Borrelli E., Montmayeur J. P., Foulkes N. S., Sassone-Corsi P. Signal transduction and gene control: the cAMP pathway. Crit Rev Oncog. 1992;3(4):321–338. [PubMed] [Google Scholar]
  6. 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]
  7. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cleveland J. L., Dean M., Rosenberg N., Wang J. Y., Rapp U. R. Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl. Mol Cell Biol. 1989 Dec;9(12):5685–5695. doi: 10.1128/mcb.9.12.5685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Darnell R. B., Boime I. Differential expression of the human gonadotropin alpha gene in ectopic and eutopic cells. Mol Cell Biol. 1985 Nov;5(11):3157–3167. doi: 10.1128/mcb.5.11.3157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ferreri K., Gill G., Montminy M. The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1210–1213. doi: 10.1073/pnas.91.4.1210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Foulkes N. S., Borrelli E., Sassone-Corsi P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell. 1991 Feb 22;64(4):739–749. doi: 10.1016/0092-8674(91)90503-q. [DOI] [PubMed] [Google Scholar]
  12. Goff S. P., Tabin C. J., Wang J. Y., Weinberg R., Baltimore D. Transfection of fibroblasts by cloned Abelson murine leukemia virus DNA and recovery of transmissible virus by recombination with helper virus. J Virol. 1982 Jan;41(1):271–285. doi: 10.1128/jvi.41.1.271-285.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gonzalez G. A., Menzel P., Leonard J., Fischer W. H., Montminy M. R. Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB. Mol Cell Biol. 1991 Mar;11(3):1306–1312. doi: 10.1128/mcb.11.3.1306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Greenberger J. S., Sakakeeny M. A., Davis L. M., Moloney W. C., Reid D. Biologic properties of factor-independent nonadherent hematopoietic and adherent preadipocyte cell lines derived from continuous bone marrow culture. Leuk Res. 1984;8(3):363–375. doi: 10.1016/0145-2126(84)90076-6. [DOI] [PubMed] [Google Scholar]
  15. Hagemeier C., Bannister A. J., Cook A., Kouzarides T. The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1580–1584. doi: 10.1073/pnas.90.4.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hunter T., Karin M. The regulation of transcription by phosphorylation. Cell. 1992 Aug 7;70(3):375–387. doi: 10.1016/0092-8674(92)90162-6. [DOI] [PubMed] [Google Scholar]
  17. Isfort R., Huhn R. D., Frackelton A. R., Jr, Ihle J. N. Stimulation of factor-dependent myeloid cell lines with interleukin 3 induces tyrosine phosphorylation of several cellular substrates. J Biol Chem. 1988 Dec 15;263(35):19203–19209. [PubMed] [Google Scholar]
  18. Josephs S. F., Wong-Staal F., Manzari V., Gallo R. C., Sodroski J. G., Trus M. D., Perkins D., Patarca R., Haseltine W. A. Long terminal repeat structure of an American isolate of type I human T-cell leukemia virus. Virology. 1984 Dec;139(2):340–345. doi: 10.1016/0042-6822(84)90379-9. [DOI] [PubMed] [Google Scholar]
  19. Kaelin W. G., Jr, Pallas D. C., DeCaprio J. A., Kaye F. J., Livingston D. M. Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 8;64(3):521–532. doi: 10.1016/0092-8674(91)90236-r. [DOI] [PubMed] [Google Scholar]
  20. Karin M. Signal transduction from cell surface to nucleus in development and disease. FASEB J. 1992 May;6(8):2581–2590. doi: 10.1096/fasebj.6.8.1317309. [DOI] [PubMed] [Google Scholar]
  21. Keller J. R., Ruscetti S. K., Ruscetti F. W. Introduction of v-abl oncogene induces monocytic differentiation of an IL-3-dependent myeloid progenitor cell line. Oncogene. 1990 Apr;5(4):549–555. [PubMed] [Google Scholar]
  22. Kim S. J., Onwuta U. S., Lee Y. I., Li R., Botchan M. R., Robbins P. D. The retinoblastoma gene product regulates Sp1-mediated transcription. Mol Cell Biol. 1992 Jun;12(6):2455–2463. doi: 10.1128/mcb.12.6.2455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kipreos E. T., Wang J. Y. Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science. 1992 Apr 17;256(5055):382–385. doi: 10.1126/science.256.5055.382. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Lafyatis R., Lechleider R., Kim S. J., Jakowlew S., Roberts A. B., Sporn M. B. Structural and functional characterization of the transforming growth factor beta 3 promoter. A cAMP-responsive element regulates basal and induced transcription. J Biol Chem. 1990 Nov 5;265(31):19128–19136. [PubMed] [Google Scholar]
  27. Landschulz W. H., Johnson P. F., McKnight S. L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988 Jun 24;240(4860):1759–1764. doi: 10.1126/science.3289117. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Montminy M. R., Bilezikjian L. M. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987 Jul 9;328(6126):175–178. doi: 10.1038/328175a0. [DOI] [PubMed] [Google Scholar]
  30. Montminy M. R., Sevarino K. A., Wagner J. A., Mandel G., Goodman R. H. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6682–6686. doi: 10.1073/pnas.83.18.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pendergast A. M., Muller A. J., Havlik M. H., Clark R., McCormick F., Witte O. N. Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5927–5931. doi: 10.1073/pnas.88.13.5927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Quinn P. G. Distinct activation domains within cAMP response element-binding protein (CREB) mediate basal and cAMP-stimulated transcription. J Biol Chem. 1993 Aug 15;268(23):16999–17009. [PubMed] [Google Scholar]
  34. 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]
  35. Renshaw M. W., Kipreos E. T., Albrecht M. R., Wang J. Y. Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth, depending on the cell context. EMBO J. 1992 Nov;11(11):3941–3951. doi: 10.1002/j.1460-2075.1992.tb05488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Risser R., Holland G. D. Structures and activities of activated abl oncogenes. Curr Top Microbiol Immunol. 1989;147:129–153. doi: 10.1007/978-3-642-74697-0_4. [DOI] [PubMed] [Google Scholar]
  37. Roberts M. S., Boundy A., O'Hare P., Pizzorno M. C., Ciufo D. M., Hayward G. S. Direct correlation between a negative autoregulatory response element at the cap site of the herpes simplex virus type 1 IE175 (alpha 4) promoter and a specific binding site for the IE175 (ICP4) protein. J Virol. 1988 Nov;62(11):4307–4320. doi: 10.1128/jvi.62.11.4307-4320.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roesler W. J., Vandenbark G. R., Hanson R. W. Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem. 1988 Jul 5;263(19):9063–9066. [PubMed] [Google Scholar]
  39. Rosenberg N., Witte O. N. Abelson murine leukemia virus mutants with alterations in the virus-specific P120 molecule. J Virol. 1980 Jan;33(1):340–348. doi: 10.1128/jvi.33.1.340-348.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rowley J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973 Jun 1;243(5405):290–293. doi: 10.1038/243290a0. [DOI] [PubMed] [Google Scholar]
  41. Sawyers C. L., Callahan W., Witte O. N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell. 1992 Sep 18;70(6):901–910. doi: 10.1016/0092-8674(92)90241-4. [DOI] [PubMed] [Google Scholar]
  42. Sheng M., Thompson M. A., Greenberg M. E. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427–1430. doi: 10.1126/science.1646483. [DOI] [PubMed] [Google Scholar]
  43. Shore S. K., Reddy E. P. Transformation of NIH3T3 cells by A-MuLV proviral DNA: effect of plasmid linearization and carrier DNA on transformation efficiency. Oncogene. 1989 Nov;4(11):1411–1413. [PubMed] [Google Scholar]
  44. Showalter S. D., Zweig M., Hampar B. Monoclonal antibodies to herpes simplex virus type 1 proteins, including the immediate-early protein ICP 4. Infect Immun. 1981 Dec;34(3):684–692. doi: 10.1128/iai.34.3.684-692.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Shtivelman E., Lifshitz B., Gale R. P., Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985 Jun 13;315(6020):550–554. doi: 10.1038/315550a0. [DOI] [PubMed] [Google Scholar]
  46. Srinivasan A., Reddy E. P., Aaronson S. A. Abelson murine leukemia virus: molecular cloning of infectious integrated proviral DNA. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2077–2081. doi: 10.1073/pnas.78.4.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Stern S., Tanaka M., Herr W. The Oct-1 homoeodomain directs formation of a multiprotein-DNA complex with the HSV transactivator VP16. Nature. 1989 Oct 19;341(6243):624–630. doi: 10.1038/341624a0. [DOI] [PubMed] [Google Scholar]
  48. Tsukada T., Horovitch S. J., Montminy M. R., Mandel G., Goodman R. H. Structure of the human vasoactive intestinal polypeptide gene. DNA. 1985 Aug;4(4):293–300. doi: 10.1089/dna.1985.4.293. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Vinson C. R., Sigler P. B., McKnight S. L. Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science. 1989 Nov 17;246(4932):911–916. doi: 10.1126/science.2683088. [DOI] [PubMed] [Google Scholar]
  51. 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]
  52. Weaver C. A., Gordon D. F., Kissil M. S., Mead D. A., Kemper B. Isolation and complete nucleotide sequence of the gene for bovine parathyroid hormone. Gene. 1984 Jun;28(3):319–329. doi: 10.1016/0378-1119(84)90149-5. [DOI] [PubMed] [Google Scholar]
  53. Welch P. J., Wang J. Y. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell. 1993 Nov 19;75(4):779–790. doi: 10.1016/0092-8674(93)90497-e. [DOI] [PubMed] [Google Scholar]
  54. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]

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