Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Jul;16(7):3853–3865. doi: 10.1128/mcb.16.7.3853

The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family.

L Galarneau 1, J F Paré 1, D Allard 1, D Hamel 1, L Levesque 1, J D Tugwood 1, S Green 1, L Bélanger 1
PMCID: PMC231382  PMID: 8668203

Abstract

The alpha1-fetoprotein (AFP) gene is located between the albumin and alpha-albumin genes and is activated by transcription factor FTF (fetoprotein transcription factor), presumed to transduce early developmental signals to the albumin gene cluster. We have identified FTF as an orphan nuclear receptor of the Drosophila FTZ-F1 family. FTF recognizes the DNA sequence 5'-TCAAGGTCA-3', the canonical recognition motif for FTZ-F1 receptors. cDNA sequence homologies indicate that rat FTF is the ortholog of mouse LRH-1 and Xenopus xFF1rA. Rodent FTF is encoded by a single-copy gene, related to the gene encoding steroidogenic factor 1 (SF-1). The 5.2-kb FTF transcript is translated from several in-frame initiator codons into FTF isoforms (54 to 64 kDa) which appear to bind DNA as monomers, with no need for a specific ligand, similar KdS (approximately equal 3 x 10(-10) M), and similar transcriptional effects. FTF activates the AFP promoter without the use of an amino-terminal activation domain; carboxy-terminus-truncated FTF exerts strong dominant negative effects. In the AFP promoter, FTF recruits an accessory trans-activator which imparts glucocorticoid reactivity upon the AFP gene. FTF binding sites are found in the promoters of other liver-expressed genes, some encoding liver transcription factors; FTF, liver alpha1-antitrypsin promoter factor LFB2, and HNF-3beta promoter factor UF2-H3beta are probably the same factor. FTF is also abundantly expressed in the pancreas and may exert differentiation functions in endodermal sublineages, similar to SF-1 in steroidogenic tissues. HepG2 hepatoma cells seem to express a mutated form of FTF.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Ang S. L., Rossant J. HNF-3 beta is essential for node and notochord formation in mouse development. Cell. 1994 Aug 26;78(4):561–574. doi: 10.1016/0092-8674(94)90522-3. [DOI] [PubMed] [Google Scholar]
  2. Ayer S., Walker N., Mosammaparast M., Nelson J. P., Shilo B. Z., Benyajati C. Activation and repression of Drosophila alcohol dehydrogenase distal transcription by two steroid hormone receptor superfamily members binding to a common response element. Nucleic Acids Res. 1993 Apr 11;21(7):1619–1627. doi: 10.1093/nar/21.7.1619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beato M., Herrlich P., Schütz G. Steroid hormone receptors: many actors in search of a plot. Cell. 1995 Dec 15;83(6):851–857. doi: 10.1016/0092-8674(95)90201-5. [DOI] [PubMed] [Google Scholar]
  4. Becker-André M., André E., DeLamarter J. F. Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem Biophys Res Commun. 1993 Aug 16;194(3):1371–1379. doi: 10.1006/bbrc.1993.1976. [DOI] [PubMed] [Google Scholar]
  5. Belanger L., Hamel D., Lachance L., Dufour D., Tremblay M., Gagnon P. M. Hormonal regulation of alpha1 foetoprotein. Nature. 1975 Aug 21;256(5519):657–659. doi: 10.1038/256657a0. [DOI] [PubMed] [Google Scholar]
  6. Bernier D., Thomassin H., Allard D., Guertin M., Hamel D., Blaquière M., Beauchemin M., LaRue H., Estable-Puig M., Bélanger L. Functional analysis of developmentally regulated chromatin-hypersensitive domains carrying the alpha 1-fetoprotein gene promoter and the albumin/alpha 1-fetoprotein intergenic enhancer. Mol Cell Biol. 1993 Mar;13(3):1619–1633. doi: 10.1128/mcb.13.3.1619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bois-Joyeux B., Denissenko M., Thomassin H., Guesdon S., Ikonomova R., Bernuau D., Feldmann G., Danan J. L. The c-jun proto-oncogene down-regulates the rat alpha-fetoprotein promoter in HepG2 hepatoma cells without binding to DNA. J Biol Chem. 1995 Apr 28;270(17):10204–10211. doi: 10.1074/jbc.270.17.10204. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Bélanger L., Roy S., Allard D. New albumin gene 3' adjacent to the alpha 1-fetoprotein locus. J Biol Chem. 1994 Feb 25;269(8):5481–5484. [PubMed] [Google Scholar]
  10. Cascio S., Zaret K. S. Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation. Development. 1991 Sep;113(1):217–225. doi: 10.1242/dev.113.1.217. [DOI] [PubMed] [Google Scholar]
  11. Chatterjee V. K., Madison L. D., Mayo S., Jameson J. L. Repression of the human glycoprotein hormone alpha-subunit gene by glucocorticoids: evidence for receptor interactions with limiting transcriptional activators. Mol Endocrinol. 1991 Jan;5(1):100–110. doi: 10.1210/mend-5-1-100. [DOI] [PubMed] [Google Scholar]
  12. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Durand B., Saunders M., Gaudon C., Roy B., Losson R., Chambon P. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J. 1994 Nov 15;13(22):5370–5382. doi: 10.1002/j.1460-2075.1994.tb06872.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dziadek M. Modulation of alphafetoprotein synthesis in the early postimplantation mouse embryo. J Embryol Exp Morphol. 1978 Aug;46:135–146. [PubMed] [Google Scholar]
  15. Ellinger-Ziegelbauer H., Gläser B., Dreyer C. A naturally occurring short variant of the FTZ-F1-related nuclear orphan receptor xFF1rA and interactions between domains of xFF1rA. Mol Endocrinol. 1995 Jul;9(7):872–886. doi: 10.1210/mend.9.7.7476970. [DOI] [PubMed] [Google Scholar]
  16. Ellinger-Ziegelbauer H., Hihi A. K., Laudet V., Keller H., Wahli W., Dreyer C. FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis. Mol Cell Biol. 1994 Apr;14(4):2786–2797. doi: 10.1128/mcb.14.4.2786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Giguère V., McBroom L. D., Flock G. Determinants of target gene specificity for ROR alpha 1: monomeric DNA binding by an orphan nuclear receptor. Mol Cell Biol. 1995 May;15(5):2517–2526. doi: 10.1128/mcb.15.5.2517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gitlin D., Perricelli A. Synthesis of serum albumin, prealbumin, alpha-foetoprotein, alpha-1-antitrypsin and transferrin by the human yolk sac. Nature. 1970 Dec 5;228(5275):995–997. doi: 10.1038/228995a0. [DOI] [PubMed] [Google Scholar]
  19. Guertin M., Baril P., Bartkowiak J., Anderson A., Bélanger L. Rapid suppression of alpha 1-fetoprotein gene transcription by dexamethasone in developing rat liver. Biochemistry. 1983 Aug 30;22(18):4296–4302. doi: 10.1021/bi00287a021. [DOI] [PubMed] [Google Scholar]
  20. Guertin M., LaRue H., Bernier D., Wrange O., Chevrette M., Gingras M. C., Bélanger L. Enhancer and promoter elements directing activation and glucocorticoid repression of the alpha 1-fetoprotein gene in hepatocytes. Mol Cell Biol. 1988 Apr;8(4):1398–1407. doi: 10.1128/mcb.8.4.1398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hazel T. G., Nathans D., Lau L. F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8444–8448. doi: 10.1073/pnas.85.22.8444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Honda S., Morohashi K., Nomura M., Takeya H., Kitajima M., Omura T. Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily. J Biol Chem. 1993 Apr 5;268(10):7494–7502. [PubMed] [Google Scholar]
  23. Houart C., Szpirer J., Szpirer C. The alpha-foetoprotein proximal enhancer: localization, cell specificity and modulation by dexamethasone. Nucleic Acids Res. 1990 Nov 11;18(21):6277–6282. doi: 10.1093/nar/18.21.6277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ikeda Y., Lala D. S., Luo X., Kim E., Moisan M. P., Parker K. L. Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol. 1993 Jul;7(7):852–860. doi: 10.1210/mend.7.7.8413309. [DOI] [PubMed] [Google Scholar]
  25. Ingraham H. A., Lala D. S., Ikeda Y., Luo X., Shen W. H., Nachtigal M. W., Abbud R., Nilson J. H., Parker K. L. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev. 1994 Oct 1;8(19):2302–2312. doi: 10.1101/gad.8.19.2302. [DOI] [PubMed] [Google Scholar]
  26. Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990 Oct 18;347(6294):645–650. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar]
  27. Jones K. A., Yamamoto K. R., Tjian R. Two distinct transcription factors bind to the HSV thymidine kinase promoter in vitro. Cell. 1985 Sep;42(2):559–572. doi: 10.1016/0092-8674(85)90113-8. [DOI] [PubMed] [Google Scholar]
  28. Koike S., Sakai M., Muramatsu M. Molecular cloning and characterization of rat estrogen receptor cDNA. Nucleic Acids Res. 1987 Mar 25;15(6):2499–2513. doi: 10.1093/nar/15.6.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kozak M. Adherence to the first-AUG rule when a second AUG codon follows closely upon the first. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2662–2666. doi: 10.1073/pnas.92.7.2662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Laimins L. A., Khoury G., Gorman C., Howard B., Gruss P. Host-specific activation of transcription by tandem repeats from simian virus 40 and Moloney murine sarcoma virus. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6453–6457. doi: 10.1073/pnas.79.21.6453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lala D. S., Rice D. A., Parker K. L. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol. 1992 Aug;6(8):1249–1258. doi: 10.1210/mend.6.8.1406703. [DOI] [PubMed] [Google Scholar]
  32. Landschulz W. H., Johnson P. F., Adashi E. Y., Graves B. J., McKnight S. L. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988 Jul;2(7):786–800. doi: 10.1101/gad.2.7.786. [DOI] [PubMed] [Google Scholar]
  33. Laudet V., Hänni C., Coll J., Catzeflis F., Stéhelin D. Evolution of the nuclear receptor gene superfamily. EMBO J. 1992 Mar;11(3):1003–1013. doi: 10.1002/j.1460-2075.1992.tb05139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lavorgna G., Karim F. D., Thummel C. S., Wu C. Potential role for a FTZ-F1 steroid receptor superfamily member in the control of Drosophila metamorphosis. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):3004–3008. doi: 10.1073/pnas.90.7.3004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lavorgna G., Ueda H., Clos J., Wu C. FTZ-F1, a steroid hormone receptor-like protein implicated in the activation of fushi tarazu. Science. 1991 May 10;252(5007):848–851. doi: 10.1126/science.1709303. [DOI] [PubMed] [Google Scholar]
  36. Le Douarin N. M. On the origin of pancreatic endocrine cells. Cell. 1988 Apr 22;53(2):169–171. doi: 10.1016/0092-8674(88)90375-3. [DOI] [PubMed] [Google Scholar]
  37. Li F. Q., Ueda H., Hirose S. Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1. Mol Cell Biol. 1994 May;14(5):3013–3021. doi: 10.1128/mcb.14.5.3013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. López-Cabrera M., Letovsky J., Hu K. Q., Siddiqui A. Multiple liver-specific factors bind to the hepatitis B virus core/pregenomic promoter: trans-activation and repression by CCAAT/enhancer binding protein. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5069–5073. doi: 10.1073/pnas.87.13.5069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mader S., Kumar V., de Verneuil H., Chambon P. Three amino acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element. Nature. 1989 Mar 16;338(6212):271–274. doi: 10.1038/338271a0. [DOI] [PubMed] [Google Scholar]
  40. Miesfeld R., Rusconi S., Godowski P. J., Maler B. A., Okret S., Wikström A. C., Gustafsson J. A., Yamamoto K. R. Genetic complementation of a glucocorticoid receptor deficiency by expression of cloned receptor cDNA. Cell. 1986 Aug 1;46(3):389–399. doi: 10.1016/0092-8674(86)90659-8. [DOI] [PubMed] [Google Scholar]
  41. Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron. 1988 May;1(3):183–188. doi: 10.1016/0896-6273(88)90138-9. [DOI] [PubMed] [Google Scholar]
  42. Monaci P., Nicosia A., Cortese R. Two different liver-specific factors stimulate in vitro transcription from the human alpha 1-antitrypsin promoter. EMBO J. 1988 Jul;7(7):2075–2087. doi: 10.1002/j.1460-2075.1988.tb03047.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Morohashi K., Honda S., Inomata Y., Handa H., Omura T. A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem. 1992 Sep 5;267(25):17913–17919. [PubMed] [Google Scholar]
  44. Nakao K., Lawless D., Ohe Y., Miyao Y., Nakabayashi H., Kamiya H., Miura K., Ohtsuka E., Tamaoki T. c-Ha-ras down regulates the alpha-fetoprotein gene but not the albumin gene in human hepatoma cells. Mol Cell Biol. 1990 Apr;10(4):1461–1469. doi: 10.1128/mcb.10.4.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nomura M., Bärtsch S., Nawata H., Omura T., Morohashi K. An E box element is required for the expression of the ad4bp gene, a mammalian homologue of ftz-f1 gene, which is essential for adrenal and gonadal development. J Biol Chem. 1995 Mar 31;270(13):7453–7461. doi: 10.1074/jbc.270.13.7453. [DOI] [PubMed] [Google Scholar]
  46. Ohno C. K., Petkovich M. FTZ-F1 beta, a novel member of the Drosophila nuclear receptor family. Mech Dev. 1993 Jan;40(1-2):13–24. doi: 10.1016/0925-4773(93)90084-b. [DOI] [PubMed] [Google Scholar]
  47. Ohno C. K., Ueda H., Petkovich M. The Drosophila nuclear receptors FTZ-F1 alpha and FTZ-F1 beta compete as monomers for binding to a site in the fushi tarazu gene. Mol Cell Biol. 1994 May;14(5):3166–3175. doi: 10.1128/mcb.14.5.3166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pani L., Quian X. B., Clevidence D., Costa R. H. The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation. Mol Cell Biol. 1992 Feb;12(2):552–562. doi: 10.1128/mcb.12.2.552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Pinkert C. A., Ornitz D. M., Brinster R. L., Palmiter R. D. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Genes Dev. 1987 May;1(3):268–276. doi: 10.1101/gad.1.3.268. [DOI] [PubMed] [Google Scholar]
  50. Renaud J. P., Rochel N., Ruff M., Vivat V., Chambon P., Gronemeyer H., Moras D. Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681–689. doi: 10.1038/378681a0. [DOI] [PubMed] [Google Scholar]
  51. Segraves W. A. Something old, some things new: the steroid receptor superfamily in Drosophila. Cell. 1991 Oct 18;67(2):225–228. doi: 10.1016/0092-8674(91)90172-u. [DOI] [PubMed] [Google Scholar]
  52. Strähle U., Schmid W., Schütz G. Synergistic action of the glucocorticoid receptor with transcription factors. EMBO J. 1988 Nov;7(11):3389–3395. doi: 10.1002/j.1460-2075.1988.tb03212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tsukiyama T., Ueda H., Hirose S., Niwa O. Embryonal long terminal repeat-binding protein is a murine homolog of FTZ-F1, a member of the steroid receptor superfamily. Mol Cell Biol. 1992 Mar;12(3):1286–1291. doi: 10.1128/mcb.12.3.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Turcotte B., Guertin M., Chevrette M., LaRue H., Bélanger L. DNase I hypersensitivity and methylation of the 5'-flanking region of the alpha 1-fetoprotein gene during developmental and glucocorticoid-induced repression of its activity in rat liver. Nucleic Acids Res. 1986 Dec 22;14(24):9827–9841. doi: 10.1093/nar/14.24.9827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Turcotte B., Meyer M. E., Bocquel M. T., Bélanger L., Chambon P. Repression of the alpha-fetoprotein gene promoter by progesterone and chimeric receptors in the presence of hormones and antihormones. Mol Cell Biol. 1990 Sep;10(9):5002–5006. doi: 10.1128/mcb.10.9.5002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Ueda H., Sun G. C., Murata T., Hirose S. A novel DNA-binding motif abuts the zinc finger domain of insect nuclear hormone receptor FTZ-F1 and mouse embryonal long terminal repeat-binding protein. Mol Cell Biol. 1992 Dec;12(12):5667–5672. doi: 10.1128/mcb.12.12.5667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Umesono K., Evans R. M. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell. 1989 Jun 30;57(7):1139–1146. doi: 10.1016/0092-8674(89)90051-2. [DOI] [PubMed] [Google Scholar]
  58. Weinstein D. C., Ruiz i Altaba A., Chen W. S., Hoodless P., Prezioso V. R., Jessell T. M., Darnell J. E., Jr The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell. 1994 Aug 26;78(4):575–588. doi: 10.1016/0092-8674(94)90523-1. [DOI] [PubMed] [Google Scholar]
  59. Wen P., Locker J. A novel hepatocytic transcription factor that binds the alpha-fetoprotein promoter-linked coupling element. Mol Cell Biol. 1994 Oct;14(10):6616–6626. doi: 10.1128/mcb.14.10.6616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wilson T. E., Fahrner T. J., Milbrandt J. The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor-DNA interaction. Mol Cell Biol. 1993 Sep;13(9):5794–5804. doi: 10.1128/mcb.13.9.5794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Zhang D. E., Ge X., Rabek J. P., Papaconstantinou J. Functional analysis of the trans-acting factor binding sites of the mouse alpha-fetoprotein proximal promoter by site-directed mutagenesis. J Biol Chem. 1991 Nov 5;266(31):21179–21185. [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES