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Gene Review

Foxe3  -  forkhead box E3

Rattus norvegicus

Synonyms: FREAC-8, Fkhl12, Forkhead box protein E3, Forkhead-related protein FKHL12, Forkhead-related transcription factor 8, ...
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Disease relevance of Foxe3

  • Analyses with the dedifferentiated hepatoma cell line HTC suggested that HNF3 alpha and/or -gamma, but not HNF3 beta, are involved in activating the tyrosine aminotransferase gene via the -11-kb enhancer [1].
  • Expression of a highly unstable and insoluble transcription factor in Escherichia coli: purification and characterization of the fork head homolog HNF3 alpha [2].

High impact information on Foxe3

  • A 110-amino-acid region in the DNA-binding domain of this family is not only very highly conserved in rodents (HNF-3 alpha, -3 beta, and -3 gamma are identical in 93 of 110 amino acids in this region) but also in Drosophila where the homeotic gene fork head has 88 of the 93 residues that are identical in the three rat genes [3].
  • The HNF-3 family in rodents is expressed in cells that derive from the lining of the primitive gut; some of the embryonic Drosophila cells in which fork head is expressed also give rise to gut and salivary glands [3].
  • Demethylation occurs within 2-3 days following rapid (< 1 h) chromatin remodeling and recruitment of a first transcription factor, HNF-3 [4].
  • HNF-6 competed with HNF-3 for binding to the same site in the CYP2C12 promoter [5].
  • The HNF-3/fkh DNA-binding domain constitutes an uncharacterized protein motif that recognizes its cognate DNA binding site as a monomer [6].

Biological context of Foxe3

  • We have cloned six forkhead gene family members from a mouse genomic library in addition to the mouse equivalents of the genes for HNF3 alpha, -beta, and -gamma [7].
  • Within this region, we have characterized two essential liver-specific enhancer domains, one of which was bound by proteins of the hepatocyte nuclear factor 3 (HNF3) family [1].
  • The cDNAs for two HNF3 beta proteins differing only in N-terminal amino acid sequences were isolated from a pancreatic cDNA library [8].
  • The HNF-3, HFH-1, and HFH-2 consensus binding sequences were also used to search DNA regulatory regions to identify potential target genes [9].
  • Binding to this region was competed by oligonucleotides corresponding to the albumin D site, but not by oligonucleotides corresponding to binding sites for the hepatocyte transcription factors HNF-1, HNF-3, HNF-4, and C/EBP [10].

Anatomical context of Foxe3

  • In line H4II, glucocorticoid induction promotes the recruitment of hepatocyte nuclear factor 3 (HNF3), presumably through the nucleosomal disruption [11].
  • We suggest that C/EBP-delta could be involved in the initial activation of epithelial progenitor cells and that HNF-3 alpha, beta, and gamma, and C/EBP-beta might participate in their maturation [12].
  • The only mRNA for a liver-enriched transcription factor not detected in the pancreas of CuD animals was HNF-3 alpha [12].
  • Expression of HNF-3 alpha, beta, and gamma, and C/EBP-beta mRNA was highly activated in proliferating liver epithelial cells on days 2 and 3 after GalN injury [12].
  • At neural plate and neural tube stages, HNF-3 beta is expressed transiently in the notochord and is then expressed by floor plate cells [13].

Associations of Foxe3 with chemical compounds

  • Our results demonstrate that 2-AAF and some of its analogs can elicit a specific mitogenic response and induce expression of the "establishment" transcription factors, HNF1 beta and HNF3 gamma, in ductal cells [14].
  • In vitro, neural plate explants are induced to express HNF-3 beta by notochord cells in a contact-dependent but cycloheximide-resistant manner, providing evidence that expression of HNF-3 beta is a direct response of neural plate cells to notochord-derived inducing signals [13].
  • HNF-3 was required for both basal transcriptional activity and stimulation of the rat CYP7A promoter activity by retinoic acid [15].
  • In attempting to explore the regulation of gene expression of HNF-3 members by physiological status, we analyzed the effects of insulin, dexamethasone and protein malnutrition on the hepatic mRNA level of each member [16].
  • Together with the DNA-sequence-binding specificity, the different response to estrogen and anti-estrogens makes our estrogen receptor fusion proteins useful tools for the investigation of the roles of HNF4, HNF3 and LFB1 in gene expression, differentiation and developmental processes [17].

Physical interactions of Foxe3


Regulatory relationships of Foxe3

  • The results reported here show that closely related members of the HNF-3/fork head gene family are expressed by axial midline cell groups involved in neural induction and patterning and suggest the involvement of these genes in the development of the vertebrate neuraxis [19].

Other interactions of Foxe3

  • Furthermore, an analysis of the DNA-binding properties of a series of HFH-1/HNF-3 beta protein chimeras has allowed us to identify a 20-amino-acid region, located adjacent to the DNA recognition helix, which contributes to DNA-binding specificity [9].
  • They express mRNAs for liver-enriched transcription factors including HNF-1 alpha, HNF-3 beta and gamma, HNF-4, and members of the CCAAT-enhancer binding protein (C/EBP) family [12].
  • This study has conclusively identified hepatocyte nuclear factor 3beta (HNF-3beta), a liver-enriched member of the HNF-3/forkhead gene family, as the predominant purified protein that interacts with the FPV motif [20].
  • Removal of the notochord in vivo prevents floor plate development and in this condition HNF-3 beta is not expressed by cells at the ventral midline of the neural tube [13].
  • Coexpression of HNF-3 beta and Isl-1/2 and mixed distribution of ventral cell types in the early neural tube [21].

Analytical, diagnostic and therapeutic context of Foxe3


  1. The distal enhancer implicated in the developmental regulation of the tyrosine aminotransferase gene is bound by liver-specific and ubiquitous factors. Nitsch, D., Schütz, G. Mol. Cell. Biol. (1993) [Pubmed]
  2. Expression of a highly unstable and insoluble transcription factor in Escherichia coli: purification and characterization of the fork head homolog HNF3 alpha. Zaret, K.S., Stevens, K. Protein Expr. Purif. (1995) [Pubmed]
  3. Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Lai, E., Prezioso, V.R., Tao, W.F., Chen, W.S., Darnell, J.E. Genes Dev. (1991) [Pubmed]
  4. Glucocorticoid-induced DNA demethylation and gene memory during development. Thomassin, H., Flavin, M., Espinás, M.L., Grange, T. EMBO J. (2001) [Pubmed]
  5. Expression of hepatocyte nuclear factor 6 in rat liver is sex-dependent and regulated by growth hormone. Lahuna, O., Fernandez, L., Karlsson, H., Maiter, D., Lemaigre, F.P., Rousseau, G.G., Gustafsson, J., Mode, A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. Clevidence, D.E., Overdier, D.G., Tao, W., Qian, X., Pani, L., Lai, E., Costa, R.H. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  7. Six members of the mouse forkhead gene family are developmentally regulated. Kaestner, K.H., Lee, K.H., Schlöndorff, J., Hiemisch, H., Monaghan, A.P., Schütz, G. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  8. Binding sites for hepatocyte nuclear factor 3 beta or 3 gamma and pancreas transcription factor 1 are required for efficient expression of the gene encoding pancreatic alpha-amylase. Cockell, M., Stolarczyk, D., Frutiger, S., Hughes, G.J., Hagenbüchle, O., Wellauer, P.K. Mol. Cell. Biol. (1995) [Pubmed]
  9. The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix. Overdier, D.G., Porcella, A., Costa, R.H. Mol. Cell. Biol. (1994) [Pubmed]
  10. Structural and functional analysis of the 5'-flanking region of the rat ceruloplasmin gene. Fleming, R.E., Gitlin, J.D. J. Biol. Chem. (1992) [Pubmed]
  11. Glucocorticoids and protein kinase A coordinately modulate transcription factor recruitment at a glucocorticoid-responsive unit. Espinás, M.L., Roux, J., Pictet, R., Grange, T. Mol. Cell. Biol. (1995) [Pubmed]
  12. Transcription factor and liver-specific mRNA expression in facultative epithelial progenitor cells of liver and pancreas. Dabeva, M.D., Hurston, E., Sharitz, D.A. Am. J. Pathol. (1995) [Pubmed]
  13. Early stages of notochord and floor plate development in the chick embryo defined by normal and induced expression of HNF-3 beta. Ruiz i Altaba, A., Placzek, M., Baldassare, M., Dodd, J., Jessell, T.M. Dev. Biol. (1995) [Pubmed]
  14. Proliferation, apoptosis, and induction of hepatic transcription factors are characteristics of the early response of biliary epithelial (oval) cells to chemical carcinogens. Bisgaard, H.C., Nagy, P., Santoni-Rugiu, E., Thorgeirsson, S.S. Hepatology (1996) [Pubmed]
  15. Transcriptional activation of the cholesterol 7alpha-hydroxylase gene (CYP7A) by nuclear hormone receptors. Crestani, M., Sadeghpour, A., Stroup, D., Galli, G., Chiang, J.Y. J. Lipid Res. (1998) [Pubmed]
  16. Gene expression of the three members of hepatocyte nuclear factor-3 is differentially regulated by nutritional and hormonal factors. Imae, M., Inoue, Y., Fu, Z., Kato, H., Noguchi, T. J. Endocrinol. (2000) [Pubmed]
  17. Estrogen-inducible derivatives of hepatocyte nuclear factor-4, hepatocyte nuclear factor-3 and liver factor B1 are differently affected by pure and partial antiestrogens. Drewes, T., Clairmont, A., Klein-Hitpass, L., Ryffel, G.U. Eur. J. Biochem. (1994) [Pubmed]
  18. Activation of surfactant protein-B transcription: signaling through the SP-A receptor utilizing the PI3 kinase pathway. Strayer, D.S., Korutla, L. J. Cell. Physiol. (2000) [Pubmed]
  19. Sequential expression of HNF-3 beta and HNF-3 alpha by embryonic organizing centers: the dorsal lip/node, notochord and floor plate. Ruiz i Altaba, A., Prezioso, V.R., Darnell, J.E., Jessell, T.M. Mech. Dev. (1993) [Pubmed]
  20. Purification and properties of rat liver nuclear proteins that interact with the hepatitis B virus enhancer 1. Kosovsky, M.J., Huan, B., Siddiqui, A. J. Biol. Chem. (1996) [Pubmed]
  21. Coexpression of HNF-3 beta and Isl-1/2 and mixed distribution of ventral cell types in the early neural tube. Ruiz i Altaba, A. Int. J. Dev. Biol. (1996) [Pubmed]
  22. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Clark, K.L., Halay, E.D., Lai, E., Burley, S.K. Nature (1993) [Pubmed]
  23. Functional dissection of the brain-specific rat aldolase C gene promoter in transgenic mice. Essential role of two GC-rich boxes and an HNF3 binding site. Thomas, M., Skala, H., Kahn, A., Tuy, F.P. J. Biol. Chem. (1995) [Pubmed]
  24. Zonal distribution of transcripts of four hepatic transcription factors in the mature rat liver. Lindros, K.O., Oinonen, T., Issakainen, J., Nagy, P., Thorgeirsson, S.S. Cell Biol. Toxicol. (1997) [Pubmed]
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