Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 May 1;88(9):3720–3724. doi: 10.1073/pnas.88.9.3720

Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity.

T Hai 1, T Curran 1
PMCID: PMC51524  PMID: 1827203

Abstract

The Fos/Jun and ATF/CREB families of transcription factors function in coupling extracellular signals to alterations in expression of specific target genes. Like many eukaryotic transcription factors, these proteins bind to DNA as dimers. Dimerization is mediated by a structure known as the "leucine-zipper" motif. Although Fos/Jun and ATF/CREB were previously thought to interact preferentially with different DNA regulatory elements (the AP-1/TRE and ATF/CRE sites, respectively), we find that members of these two families form selective cross-family heterodimers. The resulting heterodimers display distinguishable DNA binding specificities from each other and from their parental homodimers. These findings indicate that the Fos/Jun and ATF/CREB families of transcription factors are not as distinct as was previously thought. We suggest that they can be grouped into a superfamily of transcription factors.

Full text

PDF
3724

Images in this article

Selected References

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

  1. Andrisani O. M., Zhu Z. N., Pot D. A., Dixon J. E. In vitro transcription directed from the somatostatin promoter is dependent upon a purified 43-kDa DNA-binding protein. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2181–2185. doi: 10.1073/pnas.86.7.2181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrisani O., Dixon J. E. Identification and purification of a novel 120-kDa protein that recognizes the cAMP-responsive element. J Biol Chem. 1990 Feb 25;265(6):3212–3218. [PubMed] [Google Scholar]
  3. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
  4. Benbrook D. M., Jones N. C. Heterodimer formation between CREB and JUN proteins. Oncogene. 1990 Mar;5(3):295–302. [PubMed] [Google Scholar]
  5. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  6. Busch S. J., Sassone-Corsi P. Dimers, leucine zippers and DNA-binding domains. Trends Genet. 1990 Feb;6(2):36–40. doi: 10.1016/0168-9525(90)90071-d. [DOI] [PubMed] [Google Scholar]
  7. Cohen D. R., Curran T. Analysis of dimerization and DNA binding functions in Fos and Jun by domain-swapping: involvement of residues outside the leucine zipper/basic region. Oncogene. 1990 Jun;5(6):929–939. [PubMed] [Google Scholar]
  8. Cohen D. R., Ferreira P. C., Gentz R., Franza B. R., Jr, Curran T. The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes. Genes Dev. 1989 Feb;3(2):173–184. doi: 10.1101/gad.3.2.173. [DOI] [PubMed] [Google Scholar]
  9. Cortes P., Buckbinder L., Leza M. A., Rak N., Hearing P., Merino A., Reinberg D. EivF, a factor required for transcription of the adenovirus EIV promoter, binds to an element involved in EIa-dependent activation and cAMP induction. Genes Dev. 1988 Aug;2(8):975–990. doi: 10.1101/gad.2.8.975. [DOI] [PubMed] [Google Scholar]
  10. Curran T., Miller A. D., Zokas L., Verma I. M. Viral and cellular fos proteins: a comparative analysis. Cell. 1984 Feb;36(2):259–268. doi: 10.1016/0092-8674(84)90219-8. [DOI] [PubMed] [Google Scholar]
  11. Curran T., Van Beveren C., Verma I. M. Viral and cellular fos proteins are complexed with a 39,000-dalton cellular protein. Mol Cell Biol. 1985 Jan;5(1):167–172. doi: 10.1128/mcb.5.1.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Deutsch P. J., Hoeffler J. P., Jameson J. L., Habener J. F. Cyclic AMP and phorbol ester-stimulated transcription mediated by similar DNA elements that bind distinct proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7922–7926. doi: 10.1073/pnas.85.21.7922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dynan W. S. Modularity in promoters and enhancers. Cell. 1989 Jul 14;58(1):1–4. doi: 10.1016/0092-8674(89)90393-0. [DOI] [PubMed] [Google Scholar]
  14. Franza B. R., Jr, Rauscher F. J., 3rd, Josephs S. F., Curran T. The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites. Science. 1988 Mar 4;239(4844):1150–1153. doi: 10.1126/science.2964084. [DOI] [PubMed] [Google Scholar]
  15. Gaire M., Chatton B., Kedinger C. Isolation and characterization of two novel, closely related ATF cDNA clones from HeLa cells. Nucleic Acids Res. 1990 Jun 25;18(12):3467–3473. doi: 10.1093/nar/18.12.3467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gentz R., Rauscher F. J., 3rd, Abate C., Curran T. Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains. Science. 1989 Mar 31;243(4899):1695–1699. doi: 10.1126/science.2494702. [DOI] [PubMed] [Google Scholar]
  17. Gonzalez G. A., Yamamoto K. K., Fischer W. H., Karr D., Menzel P., Biggs W., 3rd, Vale W. W., Montminy M. R. A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989 Feb 23;337(6209):749–752. doi: 10.1038/337749a0. [DOI] [PubMed] [Google Scholar]
  18. Hai T. W., Liu F., Allegretto E. A., Karin M., Green M. R. A family of immunologically related transcription factors that includes multiple forms of ATF and AP-1. Genes Dev. 1988 Oct;2(10):1216–1226. doi: 10.1101/gad.2.10.1216. [DOI] [PubMed] [Google Scholar]
  19. Hai T. W., Liu F., Coukos W. J., Green M. R. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989 Dec;3(12B):2083–2090. doi: 10.1101/gad.3.12b.2083. [DOI] [PubMed] [Google Scholar]
  20. Hoeffler J. P., Meyer T. E., Yun Y., Jameson J. L., Habener J. F. Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science. 1988 Dec 9;242(4884):1430–1433. doi: 10.1126/science.2974179. [DOI] [PubMed] [Google Scholar]
  21. Hurst H. C., Jones N. C. Identification of factors that interact with the E1A-inducible adenovirus E3 promoter. Genes Dev. 1987 Dec;1(10):1132–1146. doi: 10.1101/gad.1.10.1132. [DOI] [PubMed] [Google Scholar]
  22. Ivashkiv L. B., Liou H. C., Kara C. J., Lamph W. W., Verma I. M., Glimcher L. H. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. Mol Cell Biol. 1990 Apr;10(4):1609–1621. doi: 10.1128/mcb.10.4.1609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jalinot P., Wintzerith M., Gaire M., Hauss C., Egly J. M., Kédinger C. Purification and functional characterization of a cellular transcription factor that binds to an enhancer element within the adenovirus early EIIa promoter. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2484–2488. doi: 10.1073/pnas.85.8.2484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jones N. Transcriptional regulation by dimerization: two sides to an incestuous relationship. Cell. 1990 Apr 6;61(1):9–11. doi: 10.1016/0092-8674(90)90207-u. [DOI] [PubMed] [Google Scholar]
  25. Kara C. J., Liou H. C., Ivashkiv L. B., Glimcher L. H. A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain. Mol Cell Biol. 1990 Apr;10(4):1347–1357. doi: 10.1128/mcb.10.4.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kouzarides T., Ziff E. Behind the Fos and Jun leucine zipper. Cancer Cells. 1989 Nov;1(3):71–76. [PubMed] [Google Scholar]
  27. Lee K. A., Green M. R. A cellular transcription factor E4F1 interacts with an E1a-inducible enhancer and mediates constitutive enhancer function in vitro. EMBO J. 1987 May;6(5):1345–1353. doi: 10.1002/j.1460-2075.1987.tb02374.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lee K. A., Hai T. Y., SivaRaman L., Thimmappaya B., Hurst H. C., Jones N. C., Green M. R. A cellular protein, activating transcription factor, activates transcription of multiple E1A-inducible adenovirus early promoters. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8355–8359. doi: 10.1073/pnas.84.23.8355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lee W., Mitchell P., Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987 Jun 19;49(6):741–752. doi: 10.1016/0092-8674(87)90612-x. [DOI] [PubMed] [Google Scholar]
  30. Macgregor P. F., Abate C., Curran T. Direct cloning of leucine zipper proteins: Jun binds cooperatively to the CRE with CRE-BP1. Oncogene. 1990 Apr;5(4):451–458. [PubMed] [Google Scholar]
  31. Maekawa T., Sakura H., Kanei-Ishii C., Sudo T., Yoshimura T., Fujisawa J., Yoshida M., Ishii S. Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J. 1989 Jul;8(7):2023–2028. doi: 10.1002/j.1460-2075.1989.tb03610.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. Nakabeppu Y., Ryder K., Nathans D. DNA binding activities of three murine Jun proteins: stimulation by Fos. Cell. 1988 Dec 2;55(5):907–915. doi: 10.1016/0092-8674(88)90146-8. [DOI] [PubMed] [Google Scholar]
  35. Nishina H., Sato H., Suzuki T., Sato M., Iba H. Isolation and characterization of fra-2, an additional member of the fos gene family. Proc Natl Acad Sci U S A. 1990 May;87(9):3619–3623. doi: 10.1073/pnas.87.9.3619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. O'Shea E. K., Rutkowski R., Kim P. S. Evidence that the leucine zipper is a coiled coil. Science. 1989 Jan 27;243(4890):538–542. doi: 10.1126/science.2911757. [DOI] [PubMed] [Google Scholar]
  37. O'Shea E. K., Rutkowski R., Stafford W. F., 3rd, Kim P. S. Preferential heterodimer formation by isolated leucine zippers from fos and jun. Science. 1989 Aug 11;245(4918):646–648. doi: 10.1126/science.2503872. [DOI] [PubMed] [Google Scholar]
  38. Philippe J., Missotten M. Functional characterization of a cAMP-responsive element of the rat insulin I gene. J Biol Chem. 1990 Jan 25;265(3):1465–1469. [PubMed] [Google Scholar]
  39. Rauscher F. J., 3rd, Cohen D. R., Curran T., Bos T. J., Vogt P. K., Bohmann D., Tjian R., Franza B. R., Jr Fos-associated protein p39 is the product of the jun proto-oncogene. Science. 1988 May 20;240(4855):1010–1016. doi: 10.1126/science.3130660. [DOI] [PubMed] [Google Scholar]
  40. Rauscher F. J., 3rd, Sambucetti L. C., Curran T., Distel R. J., Spiegelman B. M. Common DNA binding site for Fos protein complexes and transcription factor AP-1. Cell. 1988 Feb 12;52(3):471–480. doi: 10.1016/s0092-8674(88)80039-4. [DOI] [PubMed] [Google Scholar]
  41. Rauscher F. J., 3rd, Voulalas P. J., Franza B. R., Jr, Curran T. Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro. Genes Dev. 1988 Dec;2(12B):1687–1699. doi: 10.1101/gad.2.12b.1687. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Sheng M., McFadden G., Greenberg M. E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron. 1990 Apr;4(4):571–582. doi: 10.1016/0896-6273(90)90115-v. [DOI] [PubMed] [Google Scholar]
  44. Tan T. H., Horikoshi M., Roeder R. G. Purification and characterization of multiple nuclear factors that bind to the TAX-inducible enhancer within the human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1989 Apr;9(4):1733–1745. doi: 10.1128/mcb.9.4.1733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yamamoto K. K., Gonzalez G. A., Menzel P., Rivier J., Montminy M. R. Characterization of a bipartite activator domain in transcription factor CREB. Cell. 1990 Feb 23;60(4):611–617. doi: 10.1016/0092-8674(90)90664-z. [DOI] [PubMed] [Google Scholar]
  46. Zerial M., Toschi L., Ryseck R. P., Schuermann M., Müller R., Bravo R. The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. EMBO J. 1989 Mar;8(3):805–813. doi: 10.1002/j.1460-2075.1989.tb03441.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES