Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa, Yosuke; Nagaki, Masahito; Banno, Yoshiko; Brenner, David A.; Nozawa, Yoshinori; Moriwaki, Hisataka; Nakashima, Shigeru

doi:10.4049/jimmunol.170.8.4053

Cited by 48 publications

(65 citation statements)

References 46 publications

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“…IEX-1 as well as its rodent homologues PRG1 and gly96 represent short-lived proteins consisting of 156, 160 and 153 amino acids, respectively, and, to current knowledge, share no significant sequence similarities with any other known protein. Depending on cell type and stimulus-specific conditions, IEX-1 regulates cell growth and cellular viability (reviewed in Wu, 2003), and a significant apoptosis triggering effect by IEX-1 has been described (Scha¨fer et al, 1999;Arlt et al, 2001;Grobe et al, 2001;Schilling et al, 2001;Osawa et al, 2003;Shen et al, 2006). In the present study, we identified IEX-1 as an important mediator of G17-dependent NFkB inhibition and apoptosis in Colo320 cells expressing the wild-type CCK2 receptor.…”

Section: Introductionsupporting

confidence: 51%

The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition

et al. 2007

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Addressing the puzzling role of amidated gastrin 17 (G17) and the gastrin/CCKB/CCK2 receptor in colorectal carcinogenesis, we analysed potential candidate genes involved in G17-dependent NF-jB inhibition and apoptosis. The colorectal carcinoma cell line Colo320 overexpressing the wild-type CCK2 receptor (Colo320wt) underwent G17-induced apoptosis along with suppressed NF-jB activation and decreased expression of the antiapoptotic NF-jB target genes cIAP1 and cIAP2, whereas G17 was without effect on Colo320 cells expressing a CCK2 receptor bearing a loss of function mutation (Colo320mut). Gene microarray analysis revealed an elevated expression of the stress response gene IEX-1 in G17-treated Colo320wt but not Colo320mut cells. Quantitative real-time PCR and conventional RT-PCR confirmed this G17-dependent increase of IEX-1 expression in Colo320wt cells. If these cells were subjected to IEX-1 knockdown by small interfering RNA transfection, the apoptosis-inducing effect of G17 was abolished. Moreover, tumor necrosis factor alpha (TNFa)-or 5-FUinduced apoptosis that is greatly enhanced by G17 treatment in Colo320wt cells was prevented if IEX-1 expression was repressed. Under these conditions of blocked IEX-1 expression, the NF-jB activity remained unaffected by G17, in particular in Colo320wt cells co-treated with TNFa and also the suppressive effect of G17 on cIAP1 and cIAP2 expression was not observed anymore if IEX-1 expression was blocked. Conversely, IEX-1 overexpression in Colo320mut cells caused an increase of basal and TNFa-or 5-FU-induced apoptosis, an effect not further triggered by G17 treatment. Using a xenograft tumor model in severe combined immune deficiency mice, we could show that experimental systemic hypergastrinemia induced by the administration of omeprazole led to enhanced apoptosis as well as to a marked increase of IEX-1 expression in Colo320wt tumors, but not in Colo320mut tumors. These observations indicate that the proapoptotic effect of G17 on human colon cancer cells expressing the wild-type CCK2 receptor is mediated by IEX-1, which modulates NF-jB-dependent antiapoptotic protection and thereby exerts tumor-suppressive potential.

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Section: Introductionsupporting

confidence: 51%

The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition

et al. 2007

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“…IEX-1 enhances apoptosis in some cells, whereas in other cell systems, IEX-1 protects against apoptosis [7,8,[11][12][13]19,22,23]. Our findings show that IEX-1 may function in the control of apoptosis by directly binding to a variety of proteins associated with either the enhancement or inhibition of apoptosis and that differential binding and activation may provide an explanation for the varied effects of this protein in different cells.…”

Section: Resultsmentioning

confidence: 85%

“…The human immediate early gene X-1 (IEX-1, also known as Dif2, and murine orthologs gly96 and PRG1) plays a role in the control of apoptosis and cellular growth [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The gene (gly96) was initially identified in mouse fibroblasts as a serum-regulated, glycosylated, immediate early gene [1].…”

Section: Introductionmentioning

confidence: 99%

“…For example, in keratinocytes [22], HeLa cells [7], hepatocyte (Hc) [19], and 293 cells [8], IEX-1 increases the rate of apoptosis. With respect to the induction of apoptosis, the effect of IEX-1 can be explained partially by its inhibitory effect on survival signals.…”

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confidence: 99%

“…With respect to the induction of apoptosis, the effect of IEX-1 can be explained partially by its inhibitory effect on survival signals. There is inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt and blockade of expression of ML-1 myeloid cell leukemia gene encoded protein (MCL1), an anti-apoptotic BCL-2 family member, which is located downstream of Akt [19]. In some situations, expression of the gene in lymphocytes and Jurkat cells [11,12] results in a reduction of apoptosis and protection against TNF-induced apoptosis.…”

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Immediate early gene X-1 interacts with proteins that modulate apoptosis

Kumar¹,

Lutz²,

Frank³

et al. 2004

Biochemical and Biophysical Research Communications

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Immediate early gene X-1 (IEX-1) modulates apoptosis, cellular growth, mechanical strain-induced cardiac hypertrophy, and vascular intimal hyperplasia. To determine how IEX-1 alters apoptosis, we performed yeast two-hybrid studies using IEX-1 as the "bait" protein, and examined interactions between IEX-1 and proteins expressed by a human kidney cDNA expression library. We found that IEX-1 interacts with several proteins of which at least four are known to play a role in the regulation of apoptosis: (1) calcium-modulating cyclophilin ligand; (2) tumor necrosis factor-related apoptosisinducing ligand (tumor necrosis factor superfamily, member 10); (3) ML-1 myeloid cell leukemia gene encoded protein; and (4) BAT3, a gene present in the major histo-compatibility complex. Our data suggest that IEX-1 may regulate apoptosis by directly interacting with various proteins involved in the control of apoptotic pathways. KeywordsIEX-1; gly96; 1,25-Dihydroxyvitamin D; ApoptosisThe human immediate early gene X-1 (IEX-1, also known as Dif2, and murine orthologs gly96 and PRG1) plays a role in the control of apoptosis and cellular growth [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The gene (gly96) was initially identified in mouse fibroblasts as a serum-regulated, glycosylated, immediate early gene [1]. The messenger RNA of a similar gene (p22/PRG1) is induced in rat pancreatic cells by pituitary adenylate cyclase activating peptide (PACAP) [20]. The human ortholog of gly96 and PRG1, IEX-1, was identified as an X-radiation induced in fibroblasts by Kondratyev et al. [2], and as a UV-radiation and 1α, 25-dihydroxyvitamin D 3 -regulated gene in human keratinocytes [3,4].Increased expression of IEX-1 is associated with an increase in the growth rate of keratinocytes and HeLa cells, and disruption of IEX-1 gene expression in HeLa cells and 293 cells is associated with a decrease in cellular proliferation [3,7,8,21]. IEX-1 has been shown to be induced in cardiomyocytes and vascular smooth muscle cells by mechanical stretch, and overexpression of IEX-1 in vascular smooth muscle cells protects against stretch-induced hypertrophy [9,15] IEX-1 is regulated by a variety of factors. IEX-1 expression is increased by serum, X-, and UV-irradiation, growth factors such as epidermal growth factor, inflammatory stimuli such as lipopolysaccharide and ceramide, retinoids such as all-trans-retinoic acid or cis-retinoic acid, and by over-expression of Sp1 in cells [1][2][3]6,10,11,20,[24][25][26][27][28][29][30][31]. The gene is repressed by steroid hormones such as 1α, 25-dihydroxyvitamin D 3 and by over-expression of p53 [3,4,30,32]. 1α, 25-Dihydroxyvitamin D 3 also results in a redistribution of IEX-1 from the nucleus into the peri-nuclear and cytoplasmic space. The ratio of Sp1 to p53 within the cell appears to regulate the amount of IEX-1 expression present within the cell [30]. Slight modifications of IEX-1 transcription are observed by mutating putative elements for p300, Sox, NFκB, and AP4 within the prom...

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Determinants of breast cancer knowledge among newly diagnosed, low‐income, medically underserved women with breast cancer

Chen

Diamant

Thind

et al. 2008

Cancer

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Polypropylene (PP)‐clay nanocomposites were obtained and studied by using three different coupling agents, glycidyl methacrylate (GMA), acrylic acid (AA), and maleic anhydride (MA). Three different clays, natural montmorillonite (Cloisite Na+) and chemically modified clays Cloisite 20A and Cloisite 30B, have also been used. Nanocomposites were prepared by melt‐blending in a twin‐screw extruder using two mixing methods: two‐step mixing and one‐step mixing. The relative influence of each factor was observed from structural analysis by WAXD, POM, TEM, and mechanical properties. The results were analyzed in terms of the effect of each compatibilizing agent and incorporation method in the clay dispersion and mechanical properties of the nanocomposite. Experimental results showed that clay dispersion and interfacial adhesion are greatly affected by the kind of matrix modification. The polarity and reactivity of polar groups give as a result better interfacial adhesion and subsequent mechanical performance. PP‐g‐GMA and PP‐g‐MA were better compatibilizing agents than PP‐g‐AA. Better dispersion and exfoliation for the nanoclays were obtained when using two‐step mixing than one‐step mixing conditions. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4748–4756, 2006

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Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Cited by 48 publications

References 46 publications

The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition

The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition

Immediate early gene X-1 interacts with proteins that modulate apoptosis

Determinants of breast cancer knowledge among newly diagnosed, low‐income, medically underserved women with breast cancer

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