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. 1995 Jun 25;23(12):2206–2211. doi: 10.1093/nar/23.12.2206

Transcription of the human transferrin gene in neuronal cells.

B E Sawaya 1, E Schaeffer 1
PMCID: PMC307009  PMID: 7610049

Abstract

We have recently shown that a combination of three transcription factors governs the expression of the human transferrin gene in different brain cell types, oligodendrocytes, choroid plexus cells and neuronal cells. It was essential to elucidate the role of each factor in the regulation of transferrin gene transcription. Site-directed mutagenesis and co-transfection experiments in neuronal cells revealed that chicken ovalbumin upstream promoter transcription factor (COUP-TF), which binds to the promoter region I, acts as a repressor. Overexpression of the CCAAT/enhancer binding protein (C/EBP-alpha), which binds to the promoter region II, transactivates the -164/+1 promoter, even enables the -125/+1 region to promote transcription, and synergistically activates transcription in the presence of CREB. The C/EBP-alpha-mediated activation is antagonized by COUP-TF. The positive action of the cAMP response element-binding protein called CRI-BP is revealed by mutations of the central region I site which repress transcription. Moreover addition of dibutyryl cyclic AMP or overexpression of the catalytic subunit of protein kinase A increase transcription from the wild-type and not from the CRI mutant promoter, which shows that CRI-BP is responsible for mediating cAMP stimulation of Tf gene transcription.

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Selected References

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  1. Aldred A. R., Dickson P. W., Marley P. D., Schreiber G. Distribution of transferrin synthesis in brain and other tissues in the rat. J Biol Chem. 1987 Apr 15;262(11):5293–5297. [PubMed] [Google Scholar]
  2. Bloch B., Popovici T., Levin M. J., Tuil D., Kahn A. Transferrin gene expression visualized in oligodendrocytes of the rat brain by using in situ hybridization and immunohistochemistry. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6706–6710. doi: 10.1073/pnas.82.19.6706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boissier F., Augé-Gouillou C., Schaeffer E., Zakin M. M. The enhancer of the human transferrin gene is organized in two structural and functional domains. J Biol Chem. 1991 May 25;266(15):9822–9828. [PubMed] [Google Scholar]
  4. Brunel F., Ochoa A., Schaeffer E., Boissier F., Guillou Y., Cereghini S., Cohen G. N., Zakin M. M. Interactions of DNA-binding proteins with the 5' region of the human transferrin gene. J Biol Chem. 1988 Jul 25;263(21):10180–10185. [PubMed] [Google Scholar]
  5. Cao Z., Umek R. M., McKnight S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 Sep;5(9):1538–1552. doi: 10.1101/gad.5.9.1538. [DOI] [PubMed] [Google Scholar]
  6. Chen L. H., Bissell M. J. Transferrin mRNA level in the mouse mammary gland is regulated by pregnancy and extracellular matrix. J Biol Chem. 1987 Dec 25;262(36):17247–17250. [PubMed] [Google Scholar]
  7. Connor J. R., Menzies S. L., St Martin S. M., Mufson E. J. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990 Dec;27(4):595–611. doi: 10.1002/jnr.490270421. [DOI] [PubMed] [Google Scholar]
  8. Espinosa de los Monteros A., Kumar S., Scully S., Cole R., de Vellis J. Transferrin gene expression and secretion by rat brain cells in vitro. J Neurosci Res. 1990 Apr;25(4):576–580. doi: 10.1002/jnr.490250416. [DOI] [PubMed] [Google Scholar]
  9. Espinosa de los Monteros A., Peña L. A., de Vellis J. Does transferrin have a special role in the nervous system? J Neurosci Res. 1989 Oct;24(2):125–136. doi: 10.1002/jnr.490240202. [DOI] [PubMed] [Google Scholar]
  10. Espinosa de los Monteros A., Sawaya B. E., Guillou F., Zakin M. M., de Vellis J., Schaeffer E. Brain-specific expression of the human transferrin gene. Similar elements govern transcription in oligodendrocytes and in a neuronal cell line. J Biol Chem. 1994 Sep 30;269(39):24504–24510. [PubMed] [Google Scholar]
  11. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  12. Guillou F., Zakin M. M., Part D., Boissier F., Schaeffer E. Sertoli cell-specific expression of the human transferrin gene. Comparison with the liver-specific expression. J Biol Chem. 1991 May 25;266(15):9876–9884. [PubMed] [Google Scholar]
  13. Karpinski B. A., Morle G. D., Huggenvik J., Uhler M. D., Leiden J. M. Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4820–4824. doi: 10.1073/pnas.89.11.4820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lamph W. W., Dwarki V. J., Ofir R., Montminy M., Verma I. M. Negative and positive regulation by transcription factor cAMP response element-binding protein is modulated by phosphorylation. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4320–4324. doi: 10.1073/pnas.87.11.4320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Levin M. J., Tuil D., Uzan G., Dreyfus J. C., Kahn A. Expression of the transferrin gene during development of non-hepatic tissues: high level of transferrin mRNA in fetal muscle and adult brain. Biochem Biophys Res Commun. 1984 Jul 18;122(1):212–217. doi: 10.1016/0006-291x(84)90461-3. [DOI] [PubMed] [Google Scholar]
  16. Matsuda S., Maekawa T., Ishii S. Identification of the functional domains of the transcriptional regulator CRE-BP1. J Biol Chem. 1991 Sep 25;266(27):18188–18193. [PubMed] [Google Scholar]
  17. Mietus-Snyder M., Sladek F. M., Ginsburg G. S., Kuo C. F., Ladias J. A., Darnell J. E., Jr, Karathanasis S. K. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol. 1992 Apr;12(4):1708–1718. doi: 10.1128/mcb.12.4.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Power R. F., Lydon J. P., Conneely O. M., O'Malley B. W. Dopamine activation of an orphan of the steroid receptor superfamily. Science. 1991 Jun 14;252(5012):1546–1548. doi: 10.1126/science.2047861. [DOI] [PubMed] [Google Scholar]
  20. Sagami I., Tsai S. Y., Wang H., Tsai M. J., O'Malley B. W. Identification of two factors required for transcription of the ovalbumin gene. Mol Cell Biol. 1986 Dec;6(12):4259–4267. doi: 10.1128/mcb.6.12.4259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schaeffer E., Boissier F., Py M. C., Cohen G. N., Zakin M. M. Cell type-specific expression of the human transferrin gene. Role of promoter, negative, and enhancer elements. J Biol Chem. 1989 May 5;264(13):7153–7160. [PubMed] [Google Scholar]
  22. Schaeffer E., Guillou F., Part D., Zakin M. M. A different combination of transcription factors modulates the expression of the human transferrin promoter in liver and Sertoli cells. J Biol Chem. 1993 Nov 5;268(31):23399–23408. [PubMed] [Google Scholar]
  23. Schubert D., Heinemann S., Carlisle W., Tarikas H., Kimes B., Patrick J., Steinbach J. H., Culp W., Brandt B. L. Clonal cell lines from the rat central nervous system. Nature. 1974 May 17;249(454):224–227. doi: 10.1038/249224a0. [DOI] [PubMed] [Google Scholar]
  24. Schüle R., Evans R. M. Cross-coupling of signal transduction pathways: zinc finger meets leucine zipper. Trends Genet. 1991 Nov-Dec;7(11-12):377–381. doi: 10.1016/0168-9525(91)90259-s. [DOI] [PubMed] [Google Scholar]
  25. Skinner M. K., Griswold M. D. Sertoli cells synthesize and secrete transferrin-like protein. J Biol Chem. 1980 Oct 25;255(20):9523–9525. [PubMed] [Google Scholar]
  26. Theisen M., Behringer R. R., Cadd G. G., Brinster R. L., McKnight G. S. A C/EBP-binding site in the transferrin promoter is essential for expression in the liver but not the brain of transgenic mice. Mol Cell Biol. 1993 Dec;13(12):7666–7676. doi: 10.1128/mcb.13.12.7666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tsutsumi M., Skinner M. K., Sanders-Bush E. Transferrin gene expression and synthesis by cultured choroid plexus epithelial cells. Regulation by serotonin and cyclic adenosine 3',5'-monophosphate. J Biol Chem. 1989 Jun 5;264(16):9626–9631. [PubMed] [Google Scholar]
  28. Wang L. H., Tsai S. Y., Cook R. G., Beattie W. G., Tsai M. J., O'Malley B. W. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989 Jul 13;340(6229):163–166. doi: 10.1038/340163a0. [DOI] [PubMed] [Google Scholar]
  29. Williams S. C., Cantwell C. A., Johnson P. F. A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro. Genes Dev. 1991 Sep;5(9):1553–1567. doi: 10.1101/gad.5.9.1553. [DOI] [PubMed] [Google Scholar]
  30. 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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