Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions

Örd, Daima; Örd, Tönis

doi:10.1016/j.bbrc.2005.02.149

Cited by 96 publications

(62 citation statements)

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“…The distance from the 3′-end of the 33-bp repeats to the TSS cluster of exons 1B (slightly more than 0.3 kb) is similar to the distance between the C/EBP-ATF composite site and the TSS in the CHOP promoter (Sylvester et al, 1994), while the TSS cluster of the hTRB3 short exon 1A is located considerably closer to the 33-bp repeats (only about 0.1 kb downstream). Several transcription factors, including ATF4, CHOP and C/EBPβ, have been reported to interact with the C/EBP-ATF composite site and its flanking region within the 33-bp repeats of hTRB3, and activate the transcription of the hTRB3 gene in stressful conditions, such as the exposure of cells to arsenite, thapsigargin, hypoxia or histidinol (Ohoka et al, 2005;Örd and Örd, 2005;Rzymski et al, 2008;Su and Kilberg, 2008). In this light, it is tempting to speculate that the composition of transcription factor complexes that are bound to the 33-bp repeats determines the choice between the two TSS clusters of hTRB3 used in stressed cells.…”

Section: Discussionmentioning

confidence: 99%

“…The stress-induced synthesis of hTRB3 mRNA is initiated mainly from two separate clusters of TSS, which correspond to either the short versions of the 5′-UTR variant 1A or the variants 1B. The activation of hTRB3 transcription in response to arsenite, endoplasmic reticulum stress and hypoxia is mediated by the 33-bp tandem repeats which contain the C/EBP-ATF composite sites (Ohoka et al, 2005;Örd and Örd, 2005;Rzymski et al, 2008). The distance from the 3′-end of the 33-bp repeats to the TSS cluster of exons 1B (slightly more than 0.3 kb) is similar to the distance between the C/EBP-ATF composite site and the TSS in the CHOP promoter (Sylvester et al, 1994), while the TSS cluster of the hTRB3 short exon 1A is located considerably closer to the 33-bp repeats (only about 0.1 kb downstream).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of transcriptional induction of human or other mammalian TRB3 in response to various conditions has been investigated by several groups (Ohoka et al, 2005;Örd and Örd, 2005;Selim et al, 2007;Ding et al, 2008;Rzymski et al, 2008), but 5. A schematic representation of regulatory steps contributing to hTRB3 protein synthesis, and the expression levels and predicted protein yields of hTRB3 mRNA isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…TRB3, which acts as a feedback inhibitor of ATF4 (Ohoka et al, 2005;Örd and Örd, 2005;Jousse et al, 2007;Örd et al, 2007), the key regulator of gene expression during the integrated stress response (Harding et al, 2003), is transcriptionally induced by a variety of stresses (Bowers et al, 2003;Örd and Örd, 2003;Corcoran et al, 2005;Schwarzer et al, 2006;Yacoub Wasef et al, 2006;Jousse et al, 2007;Su and Kilberg, 2008). We have previously demonstrated the existence of a number of human (h) TRB3 mRNA isoforms, all of which contain the same coding region, but differ in their 5′ regions immediately upstream of the hTRB3 translation start codon as a result of alternative transcription initiation and alternative splicing of the first exon (Örd and Örd, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR

Örd

Kõivomägi

et al. 2009

Gene

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR

Örd

Kõivomägi

et al. 2009

Gene

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“…Thus, TRB3 is induced by stressors such as endoplasmic reticulum stress, 31,33) amino acid starvation, 34,35) hypoxia, 36,37) mitochondrial stress, 38) and insulin. 39,40) In contrast, little is known about the mechanisms regulating TRB1 induction.…”

Section: Discussionmentioning

confidence: 99%

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Miyajima

Itoh

Inoue

et al. 2015

Biological & Pharmaceutical Bulletin

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Tribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line. We found that TRB1 was strongly induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin in these cells. IL-2 expression was induced in Jurkat cells activated by PMA and ionomycin; however, knockdown of TRB1 resulted in decreased induction of IL-2. TRB1 null Jurkat cells established using the CRISPR/Cas9 system also showed reduction of IL-2 expression on PMA/ ionomycin stimulation. TRB1 knockdown also markedly inhibited IL-2 promoter activation. To determine the mechanism of the stimulatory effect on IL-2 induction, we focused on histone deacetylases (HDACs), and found that HDAC1 preferentially interacts with TRB1. TRB1 suppressed the interaction of HDAC1 with nuclear factor of activated T cells 2 (NFAT2), which is a crucial transcription factor for IL-2 induction. These results indicate that TRB1 is a positive regulator of IL-2 induction in activated T cells. Key words Tribbles 1 (TRB1); interleukin-2 (IL-2); histone deacetylase (HDAC); nuclear factor of activated T cells (NFAT)Interleukin-2 (IL-2) is a central factor in the immune system that affects various lymphocyte subsets during differentiation and in immune responses and homeostasis. 1) IL-2 is crucial for differentiation of CD4 + T cells into defined effector T cell subsets following antigen-mediated activation and for development and peripheral expansion of regulatory T (Treg) cells, which promote self-tolerance by suppressing T cell responses. For CD8 + T cells, IL-2 signaling optimizes effector T cell generation and differentiation into memory cells. 2) IL-2 is produced primarily in activated CD4+ T cells and is regulated at the mRNA level by signals from the T cell receptor (TCR) and CD28.3) Regulation of IL-2 transcription has been well characterized, and the nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) transcription factors have been shown to be essential for inducible IL-2 expression in activated T cells. [4][5][6] Activation of NFATs is mainly regulated by calcium and calcineurin, while that of AP-1 is regulated by other pathways, including the protein kinase C (PKC) and Ras-mitogen-activated protein kinase (MAPK) pathways. In response to TCR stimulation, phospholipase C γ1 (PLCγ1) is phosphorylated and activated, and subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by PLCγ1 produces inositol trisphosphate (IP3) and diacylglycerol (DAG) as second messengers. IP3 mediated Ca 2+ release from the endoplasmic reticulum (ER) and sequential entry of extracellular Ca 2+ through calcium release-activated Ca 2+ (CRAC) channels activates calcineu...

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Pathological Mutations in 5′ Untranslated Regions of Human Genes

Chatterjee

Berwal

Pal

2010

Encyclopedia of Life Sciences

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The 5′ untranslated region (5′‐UTR) of a messenger ribonucleic acid (mRNA) plays a critical role in translation regulation by influencing mRNA stability and translation efficiency. Functional elements in the 5′‐UTR such as internal ribosome entry site (IRES), upstream open reading frames (uORFs) and iron responsive element (IRE) serve to fine tune protein expression in response to cellular requirement. Genetic variations such as mutations and single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with a number of human diseases and increased susceptibility to diseases. Such pathological variations disrupt the motifs at the 5′‐UTR and cause diseases such as X‐linked Charcot‐Marie‐Tooth (CMTX) disease, multiple myeloma, hereditary hyperferritinaemia/cataract syndrome (HHCS), familial predisposition to melanoma, Marie Unna hereditary hypotrichosis (MUHH), oesophageal cancer and many others. Genetic and molecular profiling of many diseases has shown that a holistic approach of including the UTRs in regular diagnostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management. Key Concepts: 5′ Untranslated regions (UTRs) are noncoding regions of messenger RNAs (mRNAs). The 5′‐UTR is delimited by transcription initiation site at 5′ end and the physiological start codon (AUG) at the 3′ end. Motifs such as internal ribosome entry site (IRES), upstream open reading frames (uORFs), iron responsive element (IRE) and others are involved in mRNA stability and translation control. mRNAs encoding regulatory proteins need to be strongly and precisely regulated. These mRNAs are often endowed with longer than average 5′‐UTR, uORFs and stable secondary structures that regulate their translation efficiency. Mutations are changes in the DNA/genes of an organism which are heritable. Mutations that disrupt the functional elements of the 5′‐UTR are often associated with diseases. Single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with individual's drug response and disease risk.

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Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions

Cited by 96 publications

References 22 publications

Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR

Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Pathological Mutations in 5′ Untranslated Regions of Human Genes

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