Abstract
We present evidence demonstrating that the liver-enriched transcription factor HNF-3 alpha is activated upon retinoic acid-induced differentiation of mouse F9 embryonal carcinoma cells. We have detected increases in the DNA binding activity and mRNA level of HNF-3 alpha. Both are reflections of the actual activation mechanism at the level of transcriptional initiation, which we showed with the help of HNF-3 alpha promoter constructs. Time course studies clearly show that HNF-3 alpha activation is a transient event. Employing Northern blots, HNF-3 alpha mRNA can be detected between 16 and 24 hours post-differentiation, reaches its zenith at approximately 1 day, and then declines to virtually undetectable levels. F9 cells can give rise to three distinct differentiated cell types; visceral endoderm, parietal endoderm, and primitive endoderm. We have clearly shown that HNF-3 alpha stimulation occurs upon primitive endoderm formation. In addition, the transcription factor is also activated during the induction of cell lineages that give rise to parietal and visceral endoderm. HNF-3 alpha stimulation upon visceral endoderm differentiation is accompanied by the activation of HNF-3 target genes such as transthyretin, suggesting that HNF-3 alpha is involved in the developmental activation of this gene. In contrast, HNF-3 alpha target genes in parietal and primitive endoderm have yet to be identified. However, the stimulation of HNF-3 alpha during primitive endoderm formation, which is an extremely early event during murine embryogenesis, points towards a role for the factor in crucial determination processes that occur early during development.
Full text
PDF







Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berstine E. G., Hooper M. L., Grandchamp S., Ephrussi B. Alkaline phosphatase activity in mouse teratoma. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3899–3903. doi: 10.1073/pnas.70.12.3899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clevidence D. E., Overdier D. G., Tao W., Qian X., Pani L., Lai E., Costa R. H. Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3948–3952. doi: 10.1073/pnas.90.9.3948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Costa R. H., Grayson D. R., Darnell J. E., Jr Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol. 1989 Apr;9(4):1415–1425. doi: 10.1128/mcb.9.4.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Costa R. H., Van Dyke T. A., Yan C., Kuo F., Darnell J. E., Jr Similarities in transthyretin gene expression and differences in transcription factors: liver and yolk sac compared to choroid plexus. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6589–6593. doi: 10.1073/pnas.87.17.6589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dieckmann C. L., Tzagoloff A. Assembly of the mitochondrial membrane system. CBP6, a yeast nuclear gene necessary for synthesis of cytochrome b. J Biol Chem. 1985 Feb 10;260(3):1513–1520. [PubMed] [Google Scholar]
- Dirksen M. L., Jamrich M. A novel, activin-inducible, blastopore lip-specific gene of Xenopus laevis contains a fork head DNA-binding domain. Genes Dev. 1992 Apr;6(4):599–608. doi: 10.1101/gad.6.4.599. [DOI] [PubMed] [Google Scholar]
- Dony C., Kessel M., Gruss P. Post-transcriptional control of myc and p53 expression during differentiation of the embryonal carcinoma cell line F9. Nature. 1985 Oct 17;317(6038):636–639. doi: 10.1038/317636a0. [DOI] [PubMed] [Google Scholar]
- Gardner R. L. Investigation of cell lineage and differentiation in the extraembryonic endoderm of the mouse embryo. J Embryol Exp Morphol. 1982 Apr;68:175–198. [PubMed] [Google Scholar]
- Godbout R., Ingram R. S., Tilghman S. M. Fine-structure mapping of the three mouse alpha-fetoprotein gene enhancers. Mol Cell Biol. 1988 Mar;8(3):1169–1178. doi: 10.1128/mcb.8.3.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grossniklaus U., Pearson R. K., Gehring W. J. The Drosophila sloppy paired locus encodes two proteins involved in segmentation that show homology to mammalian transcription factors. Genes Dev. 1992 Jun;6(6):1030–1051. doi: 10.1101/gad.6.6.1030. [DOI] [PubMed] [Google Scholar]
- Hall R. K., Scott D. K., Noisin E. L., Lucas P. C., Granner D. K. Activation of the phosphoenolpyruvate carboxykinase gene retinoic acid response element is dependent on a retinoic acid receptor/coregulator complex. Mol Cell Biol. 1992 Dec;12(12):5527–5535. doi: 10.1128/mcb.12.12.5527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hogan B. L., Taylor A., Adamson E. Cell interactions modulate embryonal carcinoma cell differentiation into parietal or visceral endoderm. Nature. 1981 May 21;291(5812):235–237. doi: 10.1038/291235a0. [DOI] [PubMed] [Google Scholar]
- Iwai S. A., Kosaka M., Nishina Y., Sumi T., Sakuda M., Nishimune Y. Changes in Hox1.6, c-jun, and Oct-3 gene expressions are associated with teratocarcinoma F9 cell differentiation in three different ways of induction. Exp Cell Res. 1993 Mar;205(1):39–43. doi: 10.1006/excr.1993.1055. [DOI] [PubMed] [Google Scholar]
- Kuo C. J., Conley P. B., Chen L., Sladek F. M., Darnell J. E., Jr, Crabtree G. R. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. doi: 10.1038/355457a0. [DOI] [PubMed] [Google Scholar]
- Kuo C. J., Mendel D. B., Hansen L. P., Crabtree G. R. Independent regulation of HNF-1 alpha and HNF-1 beta by retinoic acid in F9 teratocarcinoma cells. EMBO J. 1991 Aug;10(8):2231–2236. doi: 10.1002/j.1460-2075.1991.tb07759.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- La Thangue N. B., Rigby P. W. The regulation of SV40 early gene expression in embryonal carcinoma stem cells--faithful transcriptional regulation in vitro. Nucleic Acids Res. 1988 Dec 23;16(24):11417–11430. doi: 10.1093/nar/16.24.11417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LaRosa G. J., Gudas L. J. Early retinoic acid-induced F9 teratocarcinoma stem cell gene ERA-1: alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Mol Cell Biol. 1988 Sep;8(9):3906–3917. doi: 10.1128/mcb.8.9.3906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lai E., Darnell J. E., Jr Transcriptional control in hepatocytes: a window on development. Trends Biochem Sci. 1991 Nov;16(11):427–430. doi: 10.1016/0968-0004(91)90169-v. [DOI] [PubMed] [Google Scholar]
- Lai E., Prezioso V. R., Smith E., Litvin O., Costa R. H., Darnell J. E., Jr HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 1990 Aug;4(8):1427–1436. doi: 10.1101/gad.4.8.1427. [DOI] [PubMed] [Google Scholar]
- Lai E., Prezioso V. R., Tao W. F., Chen W. S., Darnell J. E., Jr Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes Dev. 1991 Mar;5(3):416–427. doi: 10.1101/gad.5.3.416. [DOI] [PubMed] [Google Scholar]
- Landers J. P., Spelsberg T. C. New concepts in steroid hormone action: transcription factors, proto-oncogenes, and the cascade model for steroid regulation of gene expression. Crit Rev Eukaryot Gene Expr. 1992;2(1):19–63. [PubMed] [Google Scholar]
- Langston A. W., Gudas L. J. Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6. Mech Dev. 1992 Sep;38(3):217–227. doi: 10.1016/0925-4773(92)90055-o. [DOI] [PubMed] [Google Scholar]
- Li C., Lai C. F., Sigman D. S., Gaynor R. B. Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7739–7743. doi: 10.1073/pnas.88.17.7739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li C., Lusis A. J., Sparkes R., Tran S. M., Gaynor R. Characterization and chromosomal mapping of the gene encoding the cellular DNA binding protein HTLF. Genomics. 1992 Jul;13(3):658–664. doi: 10.1016/0888-7543(92)90138-i. [DOI] [PubMed] [Google Scholar]
- Martin G. R. Teratocarcinomas and mammalian embryogenesis. Science. 1980 Aug 15;209(4458):768–776. doi: 10.1126/science.6250214. [DOI] [PubMed] [Google Scholar]
- Miller L. M., Gallegos M. E., Morisseau B. A., Kim S. K. lin-31, a Caenorhabditis elegans HNF-3/fork head transcription factor homolog, specifies three alternative cell fates in vulval development. Genes Dev. 1993 Jun;7(6):933–947. doi: 10.1101/gad.7.6.933. [DOI] [PubMed] [Google Scholar]
- Murphy S. P., Garbern J., Odenwald W. F., Lazzarini R. A., Linney E. Differential expression of the homeobox gene Hox-1.3 in F9 embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5587–5591. doi: 10.1073/pnas.85.15.5587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pani L., Overdier D. G., Porcella A., Qian X., Lai E., Costa R. H. Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein. Mol Cell Biol. 1992 Sep;12(9):3723–3732. doi: 10.1128/mcb.12.9.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Papaioannou V. E. Lineage analysis of inner cell mass and trophectoderm using microsurgically reconstituted mouse blastocysts. J Embryol Exp Morphol. 1982 Apr;68:199–209. [PubMed] [Google Scholar]
- Piechaczyk M., Blanchard J. M., Marty L., Dani C., Panabieres F., El Sabouty S., Fort P., Jeanteur P. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucleic Acids Res. 1984 Sep 25;12(18):6951–6963. doi: 10.1093/nar/12.18.6951. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pöpperl H., Featherstone M. S. Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene. Mol Cell Biol. 1993 Jan;13(1):257–265. doi: 10.1128/mcb.13.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reichel R. R., Jacob S. T. Control of gene expression by lipophilic hormones. FASEB J. 1993 Mar;7(5):427–436. doi: 10.1096/fasebj.7.5.8385039. [DOI] [PubMed] [Google Scholar]
- Rickles R. J., Darrow A. L., Strickland S. Molecular cloning of complementary DNA to mouse tissue plasminogen activator mRNA and its expression during F9 teratocarcinoma cell differentiation. J Biol Chem. 1988 Jan 25;263(3):1563–1569. [PubMed] [Google Scholar]
- Sasaki H., Hogan B. L. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development. 1993 May;118(1):47–59. doi: 10.1242/dev.118.1.47. [DOI] [PubMed] [Google Scholar]
- Scott R. W., Vogt T. F., Croke M. E., Tilghman S. M. Tissue-specific activation of a cloned alpha-fetoprotein gene during differentiation of a transfected embryonal carcinoma cell line. Nature. 1984 Aug 16;310(5978):562–567. doi: 10.1038/310562a0. [DOI] [PubMed] [Google Scholar]
- Sejersen T., Rahm M., Szabo G., Ingvarsson S., Sümegi J. Similarities and differences in the regulation of N-myc and c-myc genes in murine embryonal carcinoma cells. Exp Cell Res. 1987 Oct;172(2):304–317. doi: 10.1016/0014-4827(87)90389-2. [DOI] [PubMed] [Google Scholar]
- Soprano D. R., Soprano K. J., Wyatt M. L., Goodman D. S. Induction of the expression of retinol-binding protein and transthyretin in F9 embryonal carcinoma cells differentiated to embryoid bodies. J Biol Chem. 1988 Dec 5;263(34):17897–17900. [PubMed] [Google Scholar]
- Strickland S., Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell. 1978 Oct;15(2):393–403. doi: 10.1016/0092-8674(78)90008-9. [DOI] [PubMed] [Google Scholar]
- Strickland S., Smith K. K., Marotti K. R. Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell. 1980 Sep;21(2):347–355. doi: 10.1016/0092-8674(80)90471-7. [DOI] [PubMed] [Google Scholar]
- Vasios G. W., Gold J. D., Petkovich M., Chambon P., Gudas L. J. A retinoic acid-responsive element is present in the 5' flanking region of the laminin B1 gene. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9099–9103. doi: 10.1073/pnas.86.23.9099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weigel D., Jäckle H. The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? Cell. 1990 Nov 2;63(3):455–456. doi: 10.1016/0092-8674(90)90439-l. [DOI] [PubMed] [Google Scholar]
- Zhu G., Muller E. G., Amacher S. L., Northrop J. L., Davis T. N. A dosage-dependent suppressor of a temperature-sensitive calmodulin mutant encodes a protein related to the fork head family of DNA-binding proteins. Mol Cell Biol. 1993 Mar;13(3):1779–1787. doi: 10.1128/mcb.13.3.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Thé H., Vivanco-Ruiz M. M., Tiollais P., Stunnenberg H., Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990 Jan 11;343(6254):177–180. doi: 10.1038/343177a0. [DOI] [PubMed] [Google Scholar]