Characterization of a novel hexameric repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that mediates 1α,25-dihydroxyvitamin D3-associated IEX-1 gene repression

Im, Hee Jeong; Craig, Theodore A.; Pittelkow, Mark R.; Kumar, Rajiv

doi:10.1038/sj.onc.1205450

Cited by 25 publications

(19 citation statements)

References 65 publications

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“…Calcitriol has been shown to decrease gene expression of Iex-1 [38]–[40]. The optimal dose of calcitriol required to reduce Iex-1 expression, 1-µM, was determined using a dose response curve.…”

Section: Resultsmentioning

confidence: 99%

The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

et al. 2014

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Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1 −/− mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1 −/− mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune-histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with calcitriol reduced Iex-1 and VNH.

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Section: Resultsmentioning

confidence: 99%

The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

et al. 2014

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“…IEX-1, as well as its rodent homologues PRG1 and gly96 (10,11), is a short lived protein consisting of 156 amino acids and shares no significant sequence similarities with any other known protein. The IEX-1 promoter is controlled by a large number of regulated transcription factors, including NF-B (6,8,12), AP1 (10,12), AP2 (10,12), VD3R (13), RAR (14), Sp1 (6,15), c-Myc (16), and p53 (6,8,15,16).…”

Section: Immediate Early Gene X-1 (Iex-1)mentioning

confidence: 99%

Immediate Early Gene X1 (IEX-1) Is Organized in Subnuclear Structures and Partially Co-localizes with Promyelocytic Leukemia Protein in HeLa Cells

Kruse

Arlt

Sieke

et al. 2005

Journal of Biological Chemistry

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Immediate early gene X1 (IEX-1) represents a stress response gene involved in growth control and modulation of apoptosis. Here, we report a detailed analysis of IEX-1 with respect to its intracellular localization. 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. This particular subnuclear localization of IEX-1 was not observed with a green fluorescent protein-IEX-1 fusion protein lacking a putative nuclear localization sequence, along with a decreased effect on apoptosis. Double immunofluorescence staining revealed a partial co-localization of endogenous promyelocytic leukemia protein (PML) and IEX-1 in these subnuclear structures. Nuclear localization of IEX-1 is also enhanced upon treatment of cells with leptomycin B, an inhibitor of the nuclear exporter CRM1. These observations indicate that IEX-1 is specifically shuttled to and from the nucleus. Overexpression experiments using PML isoforms III and IV revealed distinct intranuclear interaction of IEX-1 and PML. Coprecipitation experiments showed physical interaction between IEX-1 and PML. The close structural relation of IEX-1-containing nuclear subdomains and PML nuclear bodies suggests a function of IEX-1 related to the multiple functions of these unique subnuclear regions, particularly during stress response and growth control.

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“…It can be rapidly induced in various cells by irradiation, viral infection, inflammatory cytokines, chemical carcinogens, growth factors, and hormones under the control of transcription factors such as NF-B/rel complexes, p53, Sp1, c-Myc, and Ap-1 (12)(13)(14)(15)(16)(17)(18)(19). Like other immediate early response genes, IEX-1 plays a pivotal role in cell survival under conditions of stress (20 -22).…”

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confidence: 99%

Distinct Domains for Anti- and Pro-apoptotic Activities of IEX-1

Shen

Guo

Santos‐Berríos

et al. 2006

Journal of Biological Chemistry

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IEX-1 (immediate early response gene X-1) is a stress-inducible gene. Its overexpression can suppress or enhance apoptosis dependent on the nature of stress, yet the polypeptide does not possess any of the functional domains that are homologous to those present in well characterized effectors or inhibitors of apoptosis. This study using sequence-targeting mutagenesis reveals a transmembranelike integrated region of the protein to be critical for both pro-apoptotic and anti-apoptotic functions. Substitution of the key hydrophobic residues with hydrophilic ones within this region impairs the capacity IEX-1 to positively and negatively regulate apoptosis. Mutations at N-linked glycosylation and phosphorylation sites or truncation of the C terminus of IEX-1 also abrogated its potential to promote cell survival. However, distinguished from the transmembrane-like domain, these mutants preserved pro-apoptotic activity of IEX-1 fully. On the contrary, mutation of nuclear localization sequence, despite its importance in apoptosis, did not impede IEX-1-mediated cell survival. Strikingly, all the mutants that lose their anti-apoptotic ability are unable to prevent acute increases in production of intracellular reactive oxygen species (ROS) at the initial onset of apoptosis, whereas those mutants that can sustain antideath function also control acute ROS production as sufficiently as wild-type IEX-1. These findings suggest a critical role of IEX-1 in regulation of intracellular ROS homeostasis, providing new insight into the mechanism underlying IEX-1-mediated cell survival.A coordinated balance between cell survival and apoptosis is essential for embryonic development, tissue homeostasis, and cellular responses to various types of stress (1). Defects in this balance may contribute to a variety of diseases, including cancers, autoimmune disorders, and aberrant embryonic development (2). Programmed cell death occurs in mitochondrion-dependent and independent pathways, and the former accounts for most forms of apoptosis in response to cellular stress, loss of survival factors, and developmental cues (3, 4). The mitochondrial pathway triggers cell death as a consequence of alteration in mitochondrial membrane permeability induced by apoptotic effectors like oxidative stress and signaling-mediated translocation of Bax, Bad, Bid, or Bim, leading to the release of cytochrome c and other proteins contained in the mitochondrial intermembrane space (5, 6). Substantial evidence indicates that prior to an irreparable loss of mitochondrial structural integrity, apoptotic effectors often stimulate an acute increase in the mitochondrial membrane potential ⌬ m that facilitates the formation of reactive oxygen species (ROS), 2 the amplitude of which determines a cell to die by apoptosis or to adapt (4, 7-11). Conceivably, prevention of ROS production in the initial phase of apoptosis is essential to guard the integrity of mitochondrial membrane, protecting cells from undergoing apoptosis.IEX-1 (immediate early response gene X-1), also know...

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Characterization of a novel hexameric repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that mediates 1α,25-dihydroxyvitamin D3-associated IEX-1 gene repression

Cited by 25 publications

References 65 publications

The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

Immediate Early Gene X1 (IEX-1) Is Organized in Subnuclear Structures and Partially Co-localizes with Promyelocytic Leukemia Protein in HeLa Cells

Distinct Domains for Anti- and Pro-apoptotic Activities of IEX-1

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