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Gene Review

IER3  -  immediate early response 3

Homo sapiens

Synonyms: DIF-2, DIF2, Differentiation-dependent gene 2 protein, GLY96, IEX-1, ...
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Disease relevance of IER3


High impact information on IER3

  • This study demonstrates a key role of IEX-1L in cellular resistance to TNF-induced apoptosis [5].
  • In support, overexpression of antisense IEX-1L partially blocked TNF-induced expression of IEX-1L and sensitized normal cells to killing [5].
  • Upon phosphorylation by ERKs, IEX-1 acquires the ability to inhibit cell death induced by various stimuli [6].
  • In cells infected with herpes simplex virus 1, the RNA encoded by the stress-inducible immediate early response gene IEX-1 was up-regulated immediately after infection [7].
  • These were ARE-containing RNAs encoding IEX-1, c-fos, and IkappaBalpha and the non-ARE-containing RNAs GADD45beta and tristetraprolin [7].

Chemical compound and disease context of IER3


Biological context of IER3

  • p73beta-Mediated apoptosis requires p57kip2 induction and IEX-1 inhibition [10].
  • Immediate early gene X1 (IEX-1) represents a stress response gene involved in growth control and modulation of apoptosis [11].
  • The ability of extending life expectancy of T effectors, in line with a decrease in its expression following prolonged T cell activation, suggests a key role for IEX-1 in regulating T cell homeostasis during immune responses [1].
  • Using targeted PCR, the gene structure of PRG1, constituting 0.6 kb of the promotor region, and the DNA coding region, including a single 107-bp intron, were established from rat genomic DNA [2].
  • In addition, p300, Sox, nuclear factor-kappaB, and AP4 appear to be modulators of IEX-1 gene expression to a lesser degree [12].

Anatomical context of IER3

  • By means of confocal laser scanning microscopy, a green fluorescent protein-IEX-1 fusion protein transfected into HeLa cells, as well as endogenous IEX-1, could be detected in distinct subnuclear structures [11].
  • Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-alpha and also depend on NF-kappaB activation in Hc human hepatocytes [13].
  • Moreover, deadenylated but otherwise intact IEX-1 mRNA was readily detected in uninfected cells cultured under our experimental conditions, and its relative abundance did not increase following HSV type 1 (HSV-1) infection [4].
  • Increased levels of DIF-2 in patient leukocytes strongly correlate with severity of disease in kidney tissue [14].
  • We show that in a dose-dependent manner, UVR induces the expression of messenger RNA of a novel immediate early response gene, IEX-1, in human keratinocytes [15].

Associations of IER3 with chemical compounds

  • Nuclear localization of IEX-1 is also enhanced upon treatment of cells with leptomycin B, an inhibitor of the nuclear exporter CRM1 [11].
  • However, we report here that HSV infection does not increase the rate of degradation of IEX-1 mRNA; rather, actinomycin D chase assays indicate that the transcript is stabilized relative to that in uninfected cells in both the presence and absence of functional vhs [4].
  • Regulation of a novel immediate early response gene, IEX-1, in keratinocytes by 1alpha,25-dihydroxyvitamin D3 [16].
  • Our results indicate that DIF-2 represents a gene which is regulated in differentiation processes and strongly responsive to lipopolysaccharide, ceramide and lysophosphatidylcholine [17].
  • Our cells were not cross-resistant to faslodex, a pure antiestrogen, which moreover was inefficient in regulating IEX-1 expression [8].

Co-localisations of IER3


Regulatory relationships of IER3


Other interactions of IER3

  • Coprecipitation experiments showed physical interaction between IEX-1 and PML [11].
  • RESULTS: In DNA microarray analysis, cyclic mechanical strain at 1 Hz induced only three genes more than 2.5-fold at 3 and 6 h in THP-1 cells: prostate apoptosis response-4 (3.0-fold at 3 h, 6.7-fold at 6 h), interleukin-8 (4.3-fold at 6 h) and the immediate-early response gene, IEX-1 (2.6-fold at 6 h) [21].
  • Interestingly, NF-kappaB/rel-mediated activation of IEX-1 expression was synergized by p53, but strongly inhibited by c-Myc in a dose-dependent fashion [22].
  • In addition, DNA microarray analysis reveals that cyclic mechanical strain induces only a few genes (>2.5-fold), including interleukin-8 and IEX-1 in THP-1 cells [23].
  • Up-regulated genes included ribosomal proteins, IER3 and TPR [24].

Analytical, diagnostic and therapeutic context of IER3


  1. Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice. Zhang, Y., Schlossman, S.F., Edwards, R.A., Ou, C.N., Gu, J., Wu, M.X. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line. Schäfer, H., Trauzold, A., Siegel, E.G., Fölsch, U.R., Schmidt, W.E. Cancer Res. (1996) [Pubmed]
  3. Identification and characterization of a radiation-inducible glycosylated human early-response gene. Kondratyev, A.D., Chung, K.N., Jung, M.O. Cancer Res. (1996) [Pubmed]
  4. Herpes simplex virus infection stabilizes cellular IEX-1 mRNA. Hsu, W.L., Saffran, H.A., Smiley, J.R. J. Virol. (2005) [Pubmed]
  5. IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. Wu, M.X., Ao, Z., Prasad, K.V., Wu, R., Schlossman, S.F. Science (1998) [Pubmed]
  6. IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. Garcia, J., Ye, Y., Arranz, V., Letourneux, C., Pezeron, G., Porteu, F. EMBO J. (2002) [Pubmed]
  7. The herpes simplex virus 1 UL41 gene-dependent destabilization of cellular RNAs is selective and may be sequence-specific. Esclatine, A., Taddeo, B., Evans, L., Roizman, B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Immediate early gene X-1 (IEX-1), a hydroxytamoxifen regulated gene with increased stimulation in MCF-7 derived resistant breast cancer cells. Semlali, A., Oliva, J., Badia, E., Pons, M., Duchesne, M.J. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  9. Immediate early gene IEX-1 induces astrocytic differentiation of U87-MG human glioma cells. You, F., Osawa, Y., Hayashi, S., Nakashima, S. J. Cell. Biochem. (2007) [Pubmed]
  10. p73beta-Mediated apoptosis requires p57kip2 induction and IEX-1 inhibition. Gonzalez, S., Perez-Perez, M.M., Hernando, E., Serrano, M., Cordon-Cardo, C. Cancer Res. (2005) [Pubmed]
  11. Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells. Kruse, M.L., Arlt, A., Sieke, A., Grohmann, F., Grossmann, M., Minkenberg, J., Fölsch, U.R., Schäfer, H. J. Biol. Chem. (2005) [Pubmed]
  12. Divergent regulation of the growth-promoting gene IEX-1 by the p53 tumor suppressor and Sp1. Im, H.J., Pittelkow, M.R., Kumar, R. J. Biol. Chem. (2002) [Pubmed]
  13. Expression of the NF-kappa B target gene X-ray-inducible immediate early response factor-1 short enhances TNF-alpha-induced hepatocyte apoptosis by inhibiting Akt activation. Osawa, Y., Nagaki, M., Banno, Y., Brenner, D.A., Nozawa, Y., Moriwaki, H., Nakashima, S. J. Immunol. (2003) [Pubmed]
  14. Expression profile of leukocyte genes activated by anti-neutrophil cytoplasmic autoantibodies (ANCA). Yang, J.J., Preston, G.A., Alcorta, D.A., Waga, I., Munger, W.E., Hogan, S.L., Sekura, S.B., Phillips, B.D., Thomas, R.P., Jennette, J.C., Falk, R.J. Kidney Int. (2002) [Pubmed]
  15. A novel immediate early response gene, IEX-1, is induced by ultraviolet radiation in human keratinocytes. Kumar, R., Kobayashi, T., Warner, G.M., Wu, Y., Salisbury, J.L., Lingle, W., Pittelkow, M.R. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  16. Regulation of a novel immediate early response gene, IEX-1, in keratinocytes by 1alpha,25-dihydroxyvitamin D3. Kobayashi, T., Pittelkow, M.R., Warner, G.M., Squillace, K.A., Kumar, R. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  17. Identification and characterization of a novel monocyte/macrophage differentiation-dependent gene that is responsive to lipopolysaccharide, ceramide, and lysophosphatidylcholine. Pietzsch, A., Büchler, C., Aslanidis, C., Schmitz, G. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  18. Herpes Simplex Virus ICP27 Is Required for Virus-Induced Stabilization of the ARE-Containing IEX-1 mRNA Encoded by the Human IER3 Gene. Corcoran, J.A., Hsu, W.L., Smiley, J.R. J. Virol. (2006) [Pubmed]
  19. Thrombopoietin regulates IEX-1 gene expression through ERK-induced AML1 phosphorylation. Hamelin, V., Letourneux, C., Romeo, P.H., Porteu, F., Gaudry, M. Blood (2006) [Pubmed]
  20. Mullerian Inhibiting Substance induces NFkB signaling in breast and prostate cancer cells. Hoshiya, Y., Gupta, V., Segev, D.L., Hoshiya, M., Carey, J.L., Sasur, L.M., Tran, T.T., Ha, T.U., Maheswaran, S. Mol. Cell. Endocrinol. (2003) [Pubmed]
  21. Identification of mechanically induced genes in human monocytic cells by DNA microarrays. Ohki, R., Yamamoto, K., Mano, H., Lee, R.T., Ikeda, U., Shimada, K. J. Hypertens. (2002) [Pubmed]
  22. Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53, c-Myc, and multiple NF-kappaB/rel complexes. Huang, Y.H., Wu, J.Y., Zhang, Y., Wu, M.X. Oncogene (2002) [Pubmed]
  23. Role of mechanical stress in monocytes/macrophages: implications for atherosclerosis. Yamamoto, K., Ikeda, U., Shimada, K. Current vascular pharmacology (2003) [Pubmed]
  24. Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon. Lee, S., Bang, S., Song, K., Lee, I. Oncol. Rep. (2006) [Pubmed]
  25. The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo. Schäfer, H., Arlt, A., Trauzold, A., Hünermann-Jansen, A., Schmidt, W.E. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
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