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

Örd, Tiit; Örd, Daima; Kõivomägi, Mardo; Juhkam, Kadri; Örd, Tönis

doi:10.1016/j.gene.2009.06.001

Cited by 32 publications

(17 citation statements)

References 47 publications

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“…The numbering system in the TRB3 promoter has been established according to the identification of the transcription start sites [49]. 2XAARE- CHOP -TK-LUC and 2XAARE- ATF3 -TK-LUC plasmids was generated as previously described [10], [50].…”

Section: Methodsmentioning

confidence: 99%

Amino Acid Availability Controls TRB3 Transcription in Liver through the GCN2/eIF2α/ATF4 Pathway

et al. 2010

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In mammals, plasma amino acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that amino acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by amino acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following amino acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE) in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBPβ to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the amino acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2α/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver.

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Section: Methodsmentioning

confidence: 99%

Amino Acid Availability Controls TRB3 Transcription in Liver through the GCN2/eIF2α/ATF4 Pathway

et al. 2010

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“…There are other interesting examples of how cis -acting elements and different gene expression mechanisms can act together for a specific outcome [83]–[85] (Figure 2). In the case of the tribbles homolog 3 ( TRB3 ) gene, in response to arsenite exposure, there is binding of ATF4 to the promoter which leads to a switch in promoter usage; this results in the production of a transcript with no uORF, while under normal conditions two transcripts are produced: one with a uORF in the 5′ leader sequence and one with no uORF [83].…”

Section: Uorfs and The Cellular Response To Stress Conditionsmentioning

confidence: 99%

“…In the case of the tribbles homolog 3 ( TRB3 ) gene, in response to arsenite exposure, there is binding of ATF4 to the promoter which leads to a switch in promoter usage; this results in the production of a transcript with no uORF, while under normal conditions two transcripts are produced: one with a uORF in the 5′ leader sequence and one with no uORF [83]. For the C/EBPα gene, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) augments C/EBPα activity in acute myeloid leukemia cells by translationally enhancing the p42/p30 C/EBPα isoform ratio in a C/EBPα uORF-dependent manner [84].…”

Section: Uorfs and The Cellular Response To Stress Conditionsmentioning

confidence: 99%

Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

2013

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Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.

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“…16,17,55 TRB3 is a pseudokinase which can inhibit the activation of AKT by directly binding to AKT and, therefore, prevent the phosphorylation at Thr308 and Ser473 of AKT. 56,57 Thus, the cross-talk between the UPR and AKT pathways emerges. Similar to those effects of TG and WORT, wogonin (100 mM, for 16 h) obviously increased the levels of CHOP and TRB3 but decreased the levels of p-AKT1/2/3 (Ser473) at later stages (8-24 h).…”

Section: T He Current Strategy For Hcc Chemotherapymentioning

confidence: 99%

Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT

Zhang

et al. 2013

Hepatology Research

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

Cited by 32 publications

References 47 publications

Amino Acid Availability Controls TRB3 Transcription in Liver through the GCN2/eIF2α/ATF4 Pathway

Amino Acid Availability Controls TRB3 Transcription in Liver through the GCN2/eIF2α/ATF4 Pathway

Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT

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