Disease relevance of IER3

• Transgenic expression of IEX-1 specifically in lymphocytes impaired apoptosis in activated T cells, extended a duration of an effector-phase of a specific immune response, and increased the accumulation of effector/memory-like T cells and the susceptibility to a lupus-like autoimmune disease [1].
• Feedback-mediated hyperplasia of the rat exocrine pancreas induced by oral treatment of rats with the protease inhibitor camostate (FOY-305) was preceded by a 15-fold transient elevation of PRG1 mRNA levels [2].
• A radiation-inducible immediate-early gene, IEX-1, was identified and characterized in human squamous carcinoma cells [3].
• Herpes simplex virus infection stabilizes cellular IEX-1 mRNA [4].
• We conclude that IEX-1 mRNA is not preferentially degraded during HSV-1 infection and that HSV-1 instead inhibits the normal turnover of this mRNA [4].

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

• Immediate early gene X-1 (IEX-1), a hydroxytamoxifen regulated gene with increased stimulation in MCF-7 derived resistant breast cancer cells [8].
• Stimulation of human U87-MG glioma cells by membrane-permeable dibutyryl cAMP (dbcAMP) not only elicited their morphological changes but also induced expression of IEX-1 as well as S-100 and GFAP [9].

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

• Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells [11].

Regulatory relationships of IER3

• We conclude that IEX-1 expression in cells is regulated by the p53 tumor suppressor and Sp1, thus providing a direct mechanism for control of cell proliferation [12].
• Taken together, these data indicate that the HSV-1 immediate-early protein ICP27 alters turnover of the ARE-containing message IEX-1 by activating p38 [18].
• In contrast, morphological changes and expression of S-100 and GFAP induced by IEX-1 were not affected by H89 [9].
• The addition of TPO to UT7-Mpl cells and primary megakaryocytes induced gene expression of IEX-1 [19].
• In both breast and prostate cancer cells, MIS activated NFkB DNA binding activity and induced IEX-1, an immediate early gene which regulates cell growth and apoptosis [20].

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

• Double immunofluorescence staining revealed a partial co-localization of endogenous promyelocytic leukemia protein (PML) and IEX-1 in these subnuclear structures [11].
• Our study demonstrated an antiapoptotic effect of IEX-1 on T cell apoptosis triggered by ligation of Fas and T cell receptor (TCR)/CD3 complex [1].
• Using the mRNA differential display technique, we identified and sequenced an unknown rat gene, PACAP-responsive gene 1 (PRG1), which is highly homologous to gly96, a novel murine gene of unknown function [2].
• Utilizing an electrophoretic mobility shift assay (EMSA) and a promoter/reporter assay, we show that the NF-kappaB/rel consensus sequence in the IEX-1 promoter is specifically bound and activated by multiple NF-kappaB/rel complexes in descending order p65-c-rel-->p65-50-->p50-50 [22].
• No IEX-1L mRNA could be identified by RT-PCR analysis and subsequent DNA sequencing of total, nuclear, or cytoplasmic RNA fractions from PMA-stimulated Jurkat cells [25].

References