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. 1996 Jun 3;15(11):2771–2780.

Interaction of the co-activator CBP with Myb proteins: effects on Myb-specific transactivation and on the cooperativity with NF-M.

M Oelgeschläger 1, R Janknecht 1, J Krieg 1, S Schreek 1, B Lüscher 1
PMCID: PMC450213  PMID: 8654374

Abstract

The oncoprotein v-Myb is a potent inducer of myeloid leukemias, and its cellular homolog c-Myb plays a crucial role in the regulation of hematopoiesis. Both proteins function as transcriptional regulators. We demonstrate that this function is mediated at least in part by the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription as measured on the mim-1 promoter. In contrast, dominant negative mutants of CBP lead to repression, as does E1A, an antagonist of CBP function. Phosphorylation of c-Myb does not appear to be required for interaction with CBP, thus indicating that the binding may be constitutive. Furthermore, the C/EBP family member NF-M, which cooperates with c-Myb in transactivating the mim-1 promoter through an adjacent DNA binding site, is co-activated by CBP in a Ras-dependent manner. Not only the individual activities of c-Myb and NF-M are stimulated by CBP, but also their synergistic transcriptional function, while it is negatively regulated by dominant negative forms of CBP. These data suggest that CBP is recruited by both Myb proteins and NF-M and potentiates their transcriptional activity. We suggest that CBP can bridge between c-Myb and NF-M, thus providing an explanation for the strong synergism between these two proteins.

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Selected References

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

  1. Arany Z., Newsome D., Oldread E., Livingston D. M., Eckner R. A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. Nature. 1995 Mar 2;374(6517):81–84. doi: 10.1038/374081a0. [DOI] [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. Arias J., Alberts A. S., Brindle P., Claret F. X., Smeal T., Karin M., Feramisco J., Montminy M. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature. 1994 Jul 21;370(6486):226–229. doi: 10.1038/370226a0. [DOI] [PubMed] [Google Scholar]
  4. Aziz N., Miglarese M. R., Hendrickson R. C., Shabanowitz J., Sturgill T. W., Hunt D. F., Bender T. P. Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6429–6433. doi: 10.1073/pnas.92.14.6429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bannister A. J., Kouzarides T. CBP-induced stimulation of c-Fos activity is abrogated by E1A. EMBO J. 1995 Oct 2;14(19):4758–4762. doi: 10.1002/j.1460-2075.1995.tb00157.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Biedenkapp H., Borgmeyer U., Sippel A. E., Klempnauer K. H. Viral myb oncogene encodes a sequence-specific DNA-binding activity. Nature. 1988 Oct 27;335(6193):835–837. doi: 10.1038/335835a0. [DOI] [PubMed] [Google Scholar]
  7. Bousset K., Oelgeschläger M. H., Henriksson M., Schreek S., Burkhardt H., Litchfield D. W., Lüscher-Firzlaff J. M., Lüscher B. Regulation of transcription factors c-Myc, Max, and c-Myb by casein kinase II. Cell Mol Biol Res. 1994;40(5-6):501–511. [PubMed] [Google Scholar]
  8. Brewer C. B. Cytomegalovirus plasmid vectors for permanent lines of polarized epithelial cells. Methods Cell Biol. 1994;43(Pt A):233–245. doi: 10.1016/s0091-679x(08)60606-8. [DOI] [PubMed] [Google Scholar]
  9. Burk O., Mink S., Ringwald M., Klempnauer K. H. Synergistic activation of the chicken mim-1 gene by v-myb and C/EBP transcription factors. EMBO J. 1993 May;12(5):2027–2038. doi: 10.1002/j.1460-2075.1993.tb05852.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Chrivia J. C., Kwok R. P., Lamb N., Hagiwara M., Montminy M. R., Goodman R. H. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993 Oct 28;365(6449):855–859. doi: 10.1038/365855a0. [DOI] [PubMed] [Google Scholar]
  12. Eckner R., Ewen M. E., Newsome D., Gerdes M., DeCaprio J. A., Lawrence J. B., Livingston D. M. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 1994 Apr 15;8(8):869–884. doi: 10.1101/gad.8.8.869. [DOI] [PubMed] [Google Scholar]
  13. Gerondakis S., Bishop J. M. Structure of the protein encoded by the chicken proto-oncogene c-myb. Mol Cell Biol. 1986 Nov;6(11):3677–3684. doi: 10.1128/mcb.6.11.3677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gonzalez G. A., Montminy M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989 Nov 17;59(4):675–680. doi: 10.1016/0092-8674(89)90013-5. [DOI] [PubMed] [Google Scholar]
  15. Graf T. Myb: a transcriptional activator linking proliferation and differentiation in hematopoietic cells. Curr Opin Genet Dev. 1992 Apr;2(2):249–255. doi: 10.1016/s0959-437x(05)80281-3. [DOI] [PubMed] [Google Scholar]
  16. Harlow E., Whyte P., Franza B. R., Jr, Schley C. Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol. 1986 May;6(5):1579–1589. doi: 10.1128/mcb.6.5.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hernandez-Munain C., Krangel M. S. Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors. Mol Cell Biol. 1994 Jan;14(1):473–483. doi: 10.1128/mcb.14.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Howe K. M., Reakes C. F., Watson R. J. Characterization of the sequence-specific interaction of mouse c-myb protein with DNA. EMBO J. 1990 Jan;9(1):161–169. doi: 10.1002/j.1460-2075.1990.tb08092.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ibanez C. E., Lipsick J. S. trans activation of gene expression by v-myb. Mol Cell Biol. 1990 May;10(5):2285–2293. doi: 10.1128/mcb.10.5.2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Katz S., Kowenz-Leutz E., Müller C., Meese K., Ness S. A., Leutz A. The NF-M transcription factor is related to C/EBP beta and plays a role in signal transduction, differentiation and leukemogenesis of avian myelomonocytic cells. EMBO J. 1993 Apr;12(4):1321–1332. doi: 10.1002/j.1460-2075.1993.tb05777.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Klempnauer K. H., Arnold H., Biedenkapp H. Activation of transcription by v-myb: evidence for two different mechanisms. Genes Dev. 1989 Oct;3(10):1582–1589. doi: 10.1101/gad.3.10.1582. [DOI] [PubMed] [Google Scholar]
  22. Klempnauer K. H., Gonda T. J., Bishop J. M. Nucleotide sequence of the retroviral leukemia gene v-myb and its cellular progenitor c-myb: the architecture of a transduced oncogene. Cell. 1982 Dec;31(2 Pt 1):453–463. doi: 10.1016/0092-8674(82)90138-6. [DOI] [PubMed] [Google Scholar]
  23. Klempnauer K. H., Ramsay G., Bishop J. M., Moscovici M. G., Moscovici C., McGrath J. P., Levinson A. D. The product of the retroviral transforming gene v-myb is a truncated version of the protein encoded by the cellular oncogene c-myb. Cell. 1983 Jun;33(2):345–355. doi: 10.1016/0092-8674(83)90416-6. [DOI] [PubMed] [Google Scholar]
  24. Klempnauer K. H., Sippel A. E. The highly conserved amino-terminal region of the protein encoded by the v-myb oncogene functions as a DNA-binding domain. EMBO J. 1987 Sep;6(9):2719–2725. doi: 10.1002/j.1460-2075.1987.tb02565.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kowenz-Leutz E., Twamley G., Ansieau S., Leutz A. Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression. Genes Dev. 1994 Nov 15;8(22):2781–2791. doi: 10.1101/gad.8.22.2781. [DOI] [PubMed] [Google Scholar]
  26. Krieg J., Oelgeschläger M., Janknecht R., Lüscher B. High affinity DNA binding of native full length c-Myb and differential proteolytic sensitivity of its N- and C-terminal domains. Oncogene. 1995 Jun 1;10(11):2221–2228. [PubMed] [Google Scholar]
  27. Ku D. H., Wen S. C., Engelhard A., Nicolaides N. C., Lipson K. E., Marino T. A., Calabretta B. c-myb transactivates cdc2 expression via Myb binding sites in the 5'-flanking region of the human cdc2 gene. J Biol Chem. 1993 Jan 25;268(3):2255–2259. [PubMed] [Google Scholar]
  28. Kwok R. P., Lundblad J. R., Chrivia J. C., Richards J. P., Bächinger H. P., Brennan R. G., Roberts S. G., Green M. R., Goodman R. H. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature. 1994 Jul 21;370(6486):223–226. doi: 10.1038/370223a0. [DOI] [PubMed] [Google Scholar]
  29. Lee J. S., Galvin K. M., See R. H., Eckner R., Livingston D., Moran E., Shi Y. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 1995 May 15;9(10):1188–1198. doi: 10.1101/gad.9.10.1188. [DOI] [PubMed] [Google Scholar]
  30. Lundblad J. R., Kwok R. P., Laurance M. E., Harter M. L., Goodman R. H. Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. Nature. 1995 Mar 2;374(6517):85–88. doi: 10.1038/374085a0. [DOI] [PubMed] [Google Scholar]
  31. Lüscher B., Eisenman R. N. New light on Myc and Myb. Part II. Myb. Genes Dev. 1990 Dec;4(12B):2235–2241. doi: 10.1101/gad.4.12b.2235. [DOI] [PubMed] [Google Scholar]
  32. Nakajima T., Kinoshita S., Sasagawa T., Sasaki K., Naruto M., Kishimoto T., Akira S. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2207–2211. doi: 10.1073/pnas.90.6.2207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ness S. A., Kowenz-Leutz E., Casini T., Graf T., Leutz A. Myb and NF-M: combinatorial activators of myeloid genes in heterologous cell types. Genes Dev. 1993 May;7(5):749–759. doi: 10.1101/gad.7.5.749. [DOI] [PubMed] [Google Scholar]
  34. Ness S. A., Marknell A., Graf T. The v-myb oncogene product binds to and activates the promyelocyte-specific mim-1 gene. Cell. 1989 Dec 22;59(6):1115–1125. doi: 10.1016/0092-8674(89)90767-8. [DOI] [PubMed] [Google Scholar]
  35. Nishina Y., Nakagoshi H., Imamoto F., Gonda T. J., Ishii S. Trans-activation by the c-myb proto-oncogene. Nucleic Acids Res. 1989 Jan 11;17(1):107–117. doi: 10.1093/nar/17.1.107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Oelgeschläger M., Krieg J., Lüscher-Firzlaff J. M., Lüscher B. Casein kinase II phosphorylation site mutations in c-Myb affect DNA binding and transcriptional cooperativity with NF-M. Mol Cell Biol. 1995 Nov;15(11):5966–5974. doi: 10.1128/mcb.15.11.5966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Petrij F., Giles R. H., Dauwerse H. G., Saris J. J., Hennekam R. C., Masuno M., Tommerup N., van Ommen G. J., Goodman R. H., Peters D. J. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 1995 Jul 27;376(6538):348–351. doi: 10.1038/376348a0. [DOI] [PubMed] [Google Scholar]
  38. Ray A., Ray B. K. Serum amyloid A gene expression under acute-phase conditions involves participation of inducible C/EBP-beta and C/EBP-delta and their activation by phosphorylation. Mol Cell Biol. 1994 Jun;14(6):4324–4332. doi: 10.1128/mcb.14.6.4324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sauer F., Hansen S. K., Tjian R. Multiple TAFIIs directing synergistic activation of transcription. Science. 1995 Dec 15;270(5243):1783–1788. doi: 10.1126/science.270.5243.1783. [DOI] [PubMed] [Google Scholar]
  40. Shen-Ong G. L. The myb oncogene. Biochim Biophys Acta. 1990 Jun 1;1032(1):39–52. doi: 10.1016/0304-419x(90)90011-o. [DOI] [PubMed] [Google Scholar]
  41. Tjian R., Maniatis T. Transcriptional activation: a complex puzzle with few easy pieces. Cell. 1994 Apr 8;77(1):5–8. doi: 10.1016/0092-8674(94)90227-5. [DOI] [PubMed] [Google Scholar]
  42. Trautwein C., Caelles C., van der Geer P., Hunter T., Karin M., Chojkier M. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature. 1993 Aug 5;364(6437):544–547. doi: 10.1038/364544a0. [DOI] [PubMed] [Google Scholar]
  43. Wegner M., Cao Z., Rosenfeld M. G. Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta. Science. 1992 Apr 17;256(5055):370–373. doi: 10.1126/science.256.5055.370. [DOI] [PubMed] [Google Scholar]
  44. Wessels J. W., Mollevanger P., Dauwerse J. G., Cluitmans F. H., Breuning M. H., Beverstock G. C. Two distinct loci on the short arm of chromosome 16 are involved in myeloid leukemia. Blood. 1991 Apr 1;77(7):1555–1559. [PubMed] [Google Scholar]
  45. Weston K., Bishop J. M. Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb. Cell. 1989 Jul 14;58(1):85–93. doi: 10.1016/0092-8674(89)90405-4. [DOI] [PubMed] [Google Scholar]
  46. Whyte P., Williamson N. M., Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell. 1989 Jan 13;56(1):67–75. doi: 10.1016/0092-8674(89)90984-7. [DOI] [PubMed] [Google Scholar]
  47. Zawel L., Reinberg D. Common themes in assembly and function of eukaryotic transcription complexes. Annu Rev Biochem. 1995;64:533–561. doi: 10.1146/annurev.bi.64.070195.002533. [DOI] [PubMed] [Google Scholar]

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