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Gene Review

NFIL3  -  nuclear factor, interleukin 3 regulated

Homo sapiens

Synonyms: E4 promoter-binding protein 4, E4BP4, IL3BP1, Interleukin-3 promoter transcriptional activator, Interleukin-3-binding protein 1, ...
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Disease relevance of NFIL3

  • Exclusion of NFIL3 as the gene causing hereditary sensory neuropathy type I by mutation analysis [1].
  • The NF-IL3A protein is nearly identical to a recently identified transcriptional repressor protein, E4BP4, and NF-IL3A binds specifically to regulatory sequences in both the adenovirus E4 promoter and the human gamma interferon promoter [2].
  • Transcriptional repression of human hepatitis B virus genes by a bZIP family member, E4BP4 [3].
  • Overexpression of E4BP4 represses the stimulating activity of box alpha in the upstream regulatory sequence of the core promoter and the second enhancer in differentiated human hepatoma cell lines [3].
  • E4BP4 can also suppress the transcription of HBV genes and the production of HBV virions in a transient-transfection system that mimics the viral infection in vivo [3].

High impact information on NFIL3

  • Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes [4].
  • These results, along with the further characterization of NF-IL3-A, will contribute to the understanding of IL-3 gene regulation in stimulated T cells [5].
  • Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor [6].
  • In HepG2 cells, low levels of larger forms of E4BP4 are present that directly interact with the negative response element [6].
  • These observations implicate this binding motif in repressing both activated and basal levels of VWF transcription by different cell type-specific mechanisms, and support the hypothesis that E4BP4 sequesters negative regulators of transcription, thereby enhancing activated gene expression [6].

Biological context of NFIL3

  • This promoter is particularly responsive to TEF activation and is silenced by NFIL3, a repressor that shares the consensus binding site with PAR bZIP proteins [7].
  • Mutation analysis by direct sequencing of reverse transcription/polymerase chain reaction products from HSN-I patients excluded the coding region of the NFIL3 from being involved in the pathogenesis of HSN-I [1].
  • Furthermore, upregulation of three candidate genes (NFIL3, SKIL, and JMJD3) was shown to be dosage and time dependent with TPA treatment and was found to be directly regulated by TPA through PKC-dependent signaling [8].
  • When expressed in a transient transfection assay with a suitable reporter plasmid, E4BP4 strongly repressed transcription in a DNA-binding-site-dependent manner [9].
  • E4BP4 is a basic leucine zipper (bZIP) transcription factor that represses or activates transcription in non-osteoblastic cells [10].

Anatomical context of NFIL3


Associations of NFIL3 with chemical compounds


Physical interactions of NFIL3

  • Mutants that affect the ability of E4BP4 to bring about transcriptional repression are also deficient in their binding of Dr1 [14].
  • Competition experiment by gel shift assay indicated that E4BP4 bound specifically to CRE/ATF-like site, not NF kappa B-like site [13].

Regulatory relationships of NFIL3


Other interactions of NFIL3

  • To characterize the transcription factors in megakaryocytic cells that could bind to these two regulatory regions, we performed Northern blot analyses, which showed the presence of ets-1, elf-1 (which is thought to be restricted to T cells), NF-IL3A and AML1 mRNAs, as well as c-fos, jun B, and jun D, but not c-jun mRNA [16].
  • Although a number of nuclear proteins are able to interact with the E4BP4 repression domain in vitro, these proteins do not appear to include the general transcription factors TFIIB or TBP [17].
  • Furthermore, E4BP4 is a downstream transcriptional target of E2A-HLF [18].
  • E2A-HLF acts as a transcriptional activator and E4BP4 as a transcriptional repressor [18].
  • By DNaseI footprinting, a protection pattern was generated over the CRE/ATF-like site and the flanking sequences by bacterially produced E4BP4 [13].

Analytical, diagnostic and therapeutic context of NFIL3


  1. Exclusion of NFIL3 as the gene causing hereditary sensory neuropathy type I by mutation analysis. Hulme, D.J., Blair, I.P., Dawkins, J.L., Nicholson, G.A. Hum. Genet. (2000) [Pubmed]
  2. Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Zhang, W., Zhang, J., Kornuc, M., Kwan, K., Frank, R., Nimer, S.D. Mol. Cell. Biol. (1995) [Pubmed]
  3. Transcriptional repression of human hepatitis B virus genes by a bZIP family member, E4BP4. Lai, C.K., Ting, L.P. J. Virol. (1999) [Pubmed]
  4. Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. Ikushima, S., Inukai, T., Inaba, T., Nimer, S.D., Cleveland, J.L., Look, A.T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Transcriptional regulation of interleukin 3 gene expression in T lymphocytes. Shoemaker, S.G., Hromas, R., Kaushansky, K. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  6. Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor. Hough, C., Cuthbert, C.D., Notley, C., Brown, C., Hegadorn, C., Berber, E., Lillicrap, D. Blood (2005) [Pubmed]
  7. A Novel Role for Proline- and Acid-rich Basic Region Leucine Zipper (PAR bZIP) Proteins in the Transcriptional Regulation of a BH3-only Proapoptotic Gene. Benito, A., Gutierrez, O., Pipaon, C., Real, P.J., Gachon, F., Ritchie, A.E., Fernandez-Luna, J.L. J. Biol. Chem. (2006) [Pubmed]
  8. An efficient strategy to identify early TPA-responsive genes during differentiation of HL-60 cells. Hu, L.Y., Tepper, C.G., Lo, S.H., Lin, W.C. Gene Expr. (2006) [Pubmed]
  9. Transcriptional repression by a novel member of the bZIP family of transcription factors. Cowell, I.G., Skinner, A., Hurst, H.C. Mol. Cell. Biol. (1992) [Pubmed]
  10. Parathyroid hormone-induced E4BP4/NFIL3 down-regulates transcription in osteoblasts. Ozkurt, I.C., Tetradis, S. J. Biol. Chem. (2003) [Pubmed]
  11. E4BP4/NFIL3, a PAR-related bZIP factor with many roles. Cowell, I.G. Bioessays (2002) [Pubmed]
  12. Calcium-dependent upregulation of E4BP4 expression correlates with glucocorticoid-evoked apoptosis of human leukemic CEM cells. Priceman, S.J., Kirzner, J.D., Nary, L.J., Morris, D., Shankar, D.B., Sakamoto, K.M., Medh, R.D. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  13. Characterization of human E4BP4, a phosphorylated bZIP factor. Chen, W.J., Lewis, K.S., Chandra, G., Cogswell, J.P., Stinnett, S.W., Kadwell, S.H., Gray, J.G. Biochim. Biophys. Acta (1995) [Pubmed]
  14. Protein-protein interaction between the transcriptional repressor E4BP4 and the TBP-binding protein Dr1. Cowell, I.G., Hurst, H.C. Nucleic Acids Res. (1996) [Pubmed]
  15. Negative regulation of the osteoblast function in multiple myeloma through the repressor gene E4BP4 activated by malignant plasma cells. Silvestris, F., Cafforio, P., De Matteo, M., Calvani, N., Frassanito, M.A., Dammacco, F. Clin. Cancer Res. (2008) [Pubmed]
  16. Transcriptional regulation of interleukin-3 expression in megakaryocytes. Nimer, S., Zhang, J., Avraham, H., Miyazaki, Y. Blood (1996) [Pubmed]
  17. Transcriptional repression by the human bZIP factor E4BP4: definition of a minimal repression domain. Cowell, I.G., Hurst, H.C. Nucleic Acids Res. (1994) [Pubmed]
  18. E4BP4 expression is regulated by the t(17;19)-associated oncoprotein E2A-HLF in pro-B cells. Yeung, J., O'Sullivan, E., Hubank, M., Brady, H.J. Br. J. Haematol. (2004) [Pubmed]
  19. A novel E4BP4 element drives circadian expression of mPeriod2. Ohno, T., Onishi, Y., Ishida, N. Nucleic Acids Res. (2007) [Pubmed]
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