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. 1993 Feb;13(2):1130–1136. doi: 10.1128/mcb.13.2.1130

B-myc inhibits neoplastic transformation and transcriptional activation by c-myc.

L M Resar 1, C Dolde 1, J F Barrett 1, C V Dang 1
PMCID: PMC358997  PMID: 8423780

Abstract

B-myc is a recently described myc gene whose product has not been functionally characterized. The predicted product of B-myc is a 168-amino-acid protein with extensive homology to the c-Myc amino-terminal region, previously shown to contain a transcriptional activation domain. We hypothesized that B-Myc might also function in transcriptional regulation, although its role in regulating gene expression is predicted to be unique, because B-Myc lacks the specific DNA-binding motif found in other Myc proteins. To determine whether B-Myc could interact with the transcriptional machinery, we studied the transcriptional activation properties of a chimeric protein containing B-Myc sequences fused to the DNA-binding domain of the yeast transcriptional activator GAL4 (GAL4-B-Myc). We found that GAL4-B-Myc strongly activated expression of a GAL4-regulated reporter gene in mammalian cells. In addition, full-length B-Myc was able to inhibit or squelch reporter gene activation by a GAL4 chimeric protein containing the c-Myc transcriptional activation domain. We also observed that B-Myc dramatically inhibited the neoplastic cotransforming activity of c-Myc and activated Ras in rat embryo cells. Because B-Myc inhibits both neoplastic transformation and transcriptional activation by c-Myc, we suggest that the transforming activity of c-Myc is related to its ability to regulate transcription. Whether B-Myc functions biologically to squelch transcription and/or to regulate transcription through a specific DNA-binding protein remains unestablished.

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Selected References

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

  1. Ariga H., Imamura Y., Iguchi-Ariga S. M. DNA replication origin and transcriptional enhancer in c-myc gene share the c-myc protein binding sequences. EMBO J. 1989 Dec 20;8(13):4273–4279. doi: 10.1002/j.1460-2075.1989.tb08613.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asker C., Steinitz M., Andersson K., Sümegi J., Klein G., Ingvarsson S. Nucleotide sequence of the rat Bmyc gene. Oncogene. 1989 Dec;4(12):1523–1527. [PubMed] [Google Scholar]
  3. Blackwell T. K., Kretzner L., Blackwood E. M., Eisenman R. N., Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990 Nov 23;250(4984):1149–1151. doi: 10.1126/science.2251503. [DOI] [PubMed] [Google Scholar]
  4. Blackwood E. M., Eisenman R. N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 1991 Mar 8;251(4998):1211–1217. doi: 10.1126/science.2006410. [DOI] [PubMed] [Google Scholar]
  5. Cole M. D. Myc meets its Max. Cell. 1991 May 31;65(5):715–716. doi: 10.1016/0092-8674(91)90377-b. [DOI] [PubMed] [Google Scholar]
  6. Dang C. V., Barrett J., Villa-Garcia M., Resar L. M., Kato G. J., Fearon E. R. Intracellular leucine zipper interactions suggest c-Myc hetero-oligomerization. Mol Cell Biol. 1991 Feb;11(2):954–962. doi: 10.1128/mcb.11.2.954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dang C. V., McGuire M., Buckmire M., Lee W. M. Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein. Nature. 1989 Feb 16;337(6208):664–666. doi: 10.1038/337664a0. [DOI] [PubMed] [Google Scholar]
  8. Eilers M., Schirm S., Bishop J. M. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J. 1991 Jan;10(1):133–141. doi: 10.1002/j.1460-2075.1991.tb07929.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Flanagan P. M., Kelleher R. J., 3rd, Sayre M. H., Tschochner H., Kornberg R. D. A mediator required for activation of RNA polymerase II transcription in vitro. Nature. 1991 Apr 4;350(6317):436–438. doi: 10.1038/350436a0. [DOI] [PubMed] [Google Scholar]
  10. Gill G., Ptashne M. Negative effect of the transcriptional activator GAL4. Nature. 1988 Aug 25;334(6184):721–724. doi: 10.1038/334721a0. [DOI] [PubMed] [Google Scholar]
  11. Golemis E. A., Brent R. Fused protein domains inhibit DNA binding by LexA. Mol Cell Biol. 1992 Jul;12(7):3006–3014. doi: 10.1128/mcb.12.7.3006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Iguchi-Ariga S. M., Itani T., Kiji Y., Ariga H. Possible function of the c-myc product: promotion of cellular DNA replication. EMBO J. 1987 Aug;6(8):2365–2371. doi: 10.1002/j.1460-2075.1987.tb02513.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Iguchi-Ariga S. M., Okazaki T., Itani T., Ogata M., Sato Y., Ariga H. An initiation site of DNA replication with transcriptional enhancer activity present upstream of the c-myc gene. EMBO J. 1988 Oct;7(10):3135–3142. doi: 10.1002/j.1460-2075.1988.tb03180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ingvarsson S., Asker C., Axelson H., Klein G., Sümegi J. Structure and expression of B-myc, a new member of the myc gene family. Mol Cell Biol. 1988 Aug;8(8):3168–3174. doi: 10.1128/mcb.8.8.3168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Johnson P. F., McKnight S. L. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. doi: 10.1146/annurev.bi.58.070189.004055. [DOI] [PubMed] [Google Scholar]
  16. Kato G. J., Barrett J., Villa-Garcia M., Dang C. V. An amino-terminal c-myc domain required for neoplastic transformation activates transcription. Mol Cell Biol. 1990 Nov;10(11):5914–5920. doi: 10.1128/mcb.10.11.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kaye F., Battey J., Nau M., Brooks B., Seifter E., De Greve J., Birrer M., Sausville E., Minna J. Structure and expression of the human L-myc gene reveal a complex pattern of alternative mRNA processing. Mol Cell Biol. 1988 Jan;8(1):186–195. doi: 10.1128/mcb.8.1.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kingston R. E., Baldwin A. S., Jr, Sharp P. A. Regulation of heat shock protein 70 gene expression by c-myc. Nature. 1984 Nov 15;312(5991):280–282. doi: 10.1038/312280a0. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Lech K., Anderson K., Brent R. DNA-bound Fos proteins activate transcription in yeast. Cell. 1988 Jan 29;52(2):179–184. doi: 10.1016/0092-8674(88)90506-5. [DOI] [PubMed] [Google Scholar]
  21. Lillie J. W., Green M. R. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. doi: 10.1038/338039a0. [DOI] [PubMed] [Google Scholar]
  22. Lin Y. S., Green M. R. Mechanism of action of an acidic transcriptional activator in vitro. Cell. 1991 Mar 8;64(5):971–981. doi: 10.1016/0092-8674(91)90321-o. [DOI] [PubMed] [Google Scholar]
  23. Lüscher B., Eisenman R. N. New light on Myc and Myb. Part I. Myc. Genes Dev. 1990 Dec;4(12A):2025–2035. doi: 10.1101/gad.4.12a.2025. [DOI] [PubMed] [Google Scholar]
  24. Martin K. J., Lillie J. W., Green M. R. Evidence for interaction of different eukaryotic transcriptional activators with distinct cellular targets. Nature. 1990 Jul 12;346(6280):147–152. doi: 10.1038/346147a0. [DOI] [PubMed] [Google Scholar]
  25. Martin K. J. The interactions of transcription factors and their adaptors, coactivators and accessory proteins. Bioessays. 1991 Oct;13(10):499–503. doi: 10.1002/bies.950131003. [DOI] [PubMed] [Google Scholar]
  26. Meyer M. E., Gronemeyer H., Turcotte B., Bocquel M. T., Tasset D., Chambon P. Steroid hormone receptors compete for factors that mediate their enhancer function. Cell. 1989 May 5;57(3):433–442. doi: 10.1016/0092-8674(89)90918-5. [DOI] [PubMed] [Google Scholar]
  27. Nau M. M., Brooks B. J., Battey J., Sausville E., Gazdar A. F., Kirsch I. R., McBride O. W., Bertness V., Hollis G. F., Minna J. D. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature. 1985 Nov 7;318(6041):69–73. doi: 10.1038/318069a0. [DOI] [PubMed] [Google Scholar]
  28. Onclercq R., Gilardi P., Lavenu A., Cremisi C. c-myc products trans-activate the adenovirus E4 promoter in EC stem cells by using the same target sequence as E1A products. J Virol. 1988 Dec;62(12):4533–4537. doi: 10.1128/jvi.62.12.4533-4537.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Prendergast G. C., Cole M. D. Posttranscriptional regulation of cellular gene expression by the c-myc oncogene. Mol Cell Biol. 1989 Jan;9(1):124–134. doi: 10.1128/mcb.9.1.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Prendergast G. C., Lawe D., Ziff E. B. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell. 1991 May 3;65(3):395–407. doi: 10.1016/0092-8674(91)90457-a. [DOI] [PubMed] [Google Scholar]
  31. Prendergast G. C., Ziff E. B. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science. 1991 Jan 11;251(4990):186–189. doi: 10.1126/science.1987636. [DOI] [PubMed] [Google Scholar]
  32. Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. doi: 10.1038/335683a0. [DOI] [PubMed] [Google Scholar]
  33. Pugh B. F., Tjian R. Diverse transcriptional functions of the multisubunit eukaryotic TFIID complex. J Biol Chem. 1992 Jan 15;267(2):679–682. [PubMed] [Google Scholar]
  34. Seed B., Sheen J. Y. A simple phase-extraction assay for chloramphenicol acyltransferase activity. Gene. 1988 Jul 30;67(2):271–277. doi: 10.1016/0378-1119(88)90403-9. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Stone J., de Lange T., Ramsay G., Jakobovits E., Bishop J. M., Varmus H., Lee W. Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol Cell Biol. 1987 May;7(5):1697–1709. doi: 10.1128/mcb.7.5.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stringer K. F., Ingles C. J., Greenblatt J. Direct and selective binding of an acidic transcriptional activation domain to the TATA-box factor TFIID. Nature. 1990 Jun 28;345(6278):783–786. doi: 10.1038/345783a0. [DOI] [PubMed] [Google Scholar]
  38. Sugden B., Marsh K., Yates J. A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein-Barr virus. Mol Cell Biol. 1985 Feb;5(2):410–413. doi: 10.1128/mcb.5.2.410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vennstrom B., Sheiness D., Zabielski J., Bishop J. M. Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol. 1982 Jun;42(3):773–779. doi: 10.1128/jvi.42.3.773-779.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]

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