The structure of the 5′-end of the protein-tyrosine phosphatase PTPRJ mRNA reveals a novel mechanism for translation attenuation

Karagyozov, Luchezar; Godfrey, Rinesh; Böhmer, Sylvia‐Annette; Petermann, Astrid; Hölters, Sebastian; Östman, Arne; Böhmer, Frank‐D.

doi:10.1093/nar/gkn391

Cited by 18 publications

(29 citation statements)

References 31 publications

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“…Translational inhibition by uORFs in some eukaryotic transcripts is dependent upon the peptide-coding sequence of the uORF (Karagyozov et al 2008;Wei et al 2012). Based on these data, and knowing that the peptide encoded by the EPO uORF is conserved among mammalian species (Fig.…”

Section: Translational Repression Exerted By the Epo Uorf Is Peptide mentioning

confidence: 99%

Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia

Barbosa

Romão²

2014

RNA

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Erythropoietin (EPO) is a key mediator hormone for hypoxic induction of erythropoiesis that also plays important nonhematopoietic functions. It has been shown that EPO gene expression regulation occurs at different levels, including transcription and mRNA stabilization. In this report, we show that expression of EPO is also regulated at the translational level by an upstream open reading frame (uORF) of 14 codons. As judged by comparisons of protein and mRNA levels, the uORF acts as a cis-acting element that represses translation of the main EPO ORF in unstressed HEK293, HepG2, and HeLa cells. However, in response to hypoxia, this repression is significantly released, specifically in HeLa cells, through a mechanism that involves processive scanning of ribosomes from the 5 ′ end of the EPO transcript and enhanced ribosome bypass of the uORF. In addition, we demonstrate that in HeLa cells, hypoxia induces the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) concomitantly with a significant increase of EPO protein synthesis. These findings provide a framework for understanding that production of high levels of EPO induced by hypoxia also involves regulation at the translational level.

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Section: Translational Repression Exerted By the Epo Uorf Is Peptide mentioning

confidence: 99%

Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia

Barbosa

Romão²

2014

RNA

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“…Plasmids encoding WT hFLT3, hFLT3 ITD, 18 and HA-tagged hDEP-1 21 were previously described. The human NOX4 expression construct was a kind gift of Dr David Lambeth (Emory University Medical School, Atlanta, GA).…”

Section: Dna Constructsmentioning

confidence: 99%

“…A full-length PTPRJ-promoter reporter construct was previously described. 21 shRNA constructs for knockdown of endogenous DEP-1 in 32D cells were previously reported. 20 …”

Section: Dna Constructsmentioning

confidence: 99%

Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ

Godfrey

Arora

Bauer

et al. 2012

Blood

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Signal transduction of FMS-like tyrosine kinase 3 (FLT3) is regulated by proteintyrosine phosphatases (PTPs). IntroductionAcute myeloid leukemia (AML) is the most frequent leukemia in adults with improving but still limited treatment possibilities, notably in elderly patients. 1,2 It arises by malignant transformation of myeloid progenitor cells. Among the contributing genetic lesions, mutations in the class III receptor tyrosine kinase (RTK) FMS-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients. 3 The prevalent type of FLT3 mutations are internal tandem duplications (ITD) of amino acid stretches in the juxtamembrane domain or in the tyrosine kinase domain, 4,5 which confer cytokineindependent proliferation and resistance to apoptosis, and causally contribute to AML in combination with additional genetic lesions. 1 Compared with the ligand-activated wild-type (WT) FLT3, FLT3 ITD mutants exhibit not only elevated but also altered signaling quality, with very pronounced activation of signal transducer and activator of transcription (STAT)5 as one characteristic feature. 6,7 FLT3 ITD also causes the production of high levels of reactive oxygen species (ROS). 8,9 Signal transduction of RTKs is regulated by protein-tyrosine phosphatases (PTPs). PTPs prevent ligand-independent RTK activation, and contribute to modulation and termination of ligand-induced signaling. 10 The activity of PTPs is regulated at several different levels. 11 One regulatory principle is the reversible oxidation of the PTP active-site cysteine, which leads to reversible inactivation. 12,13 Temporary inactivation of negatively regulating PTPs by this mechanism is believed to be important for efficient RTK signal propagation in the cell. 14 A major ROS causing cellular PTP oxidation is hydrogen peroxide (H 2 O 2 ), which can be generated by a dismutase reaction from superoxide anions, the reaction products of NADPH-oxidases. Activation of the NADPH oxidase isoform 1 (NOX1) occurs downstream of RTK activation, and involves activation and membrane translocation of the small guanosine triphosphate (GTP)ase Rac1. 15 ROS generation in the cell is counteracted by efficient ROS decomposing systems. 16 These include peroxiredoxins (Prx), which have a very low K m for H 2 O 2 and can eliminate it even at low concentrations. 17 Relatively little is known about PTPs regulating FLT3 signal transduction. We have previously shown that the nontransmembrane PTPs PTP1B and SHP-1 can potently dephosphorylate FLT3 on overexpression. Further, PTP1B appears important for suppressing signaling of newly synthesized FLT3. 7,18 SHP-2 acts as a positive regulator, because it is important for Erk activation and proliferation induced by ligand-activated WT FLT3. However, it is dispensable for FLT3 ITD-mediated transformation. 19 We previously performed a shRNA-based screen to identify PTPs regulating WT FLT3. The initial screen assessed the effects of shRNAs for 20 PTPs on FL-induced Erk1/2 activation in WT FLT3-expressing 32D cells. Among several potentia...

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“…Little is known about the molecular mechanism underlying the regulation of Ptprj expression. Although there is little data on regulation of transcription, the 5′ end of the mRNA is thought to attenuate translation [33].…”

Section: Introductionmentioning

confidence: 99%

Regulated Expression of PTPRJ/CD148 and an Antisense Long Noncoding RNA in Macrophages by Proinflammatory Stimuli

et al. 2013

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PTPRJ/CD148 is a tyrosine phosphatase that has tumour suppressor-like activity. Quantitative PCR of various cells and tissues revealed that it is preferentially expressed in macrophage-enriched tissues. Within lymphoid tissues immunohistochemistry revealed that PTPRJ/CD148 co-localised with F4/80, indicating that macrophages most strongly express the protein. Macrophages express the highest basal level of ptprj, and this is elevated further by treatment with LPS and other Toll-like receptor ligands. In contrast, CSF-1 treatment reduced basal and stimulated Ptprj expression in human and mouse cells, and interferon also repressed Ptprj expression. We identified a 1006 nucleotide long noncoding RNA species, Ptprj-as1 that is transcribed antisense to Ptprj. Ptprj-as1 was highly expressed in macrophage-enriched tissue and was transiently induced by Toll-like receptor ligands with a similar time course to Ptprj. Finally, putative transcription factor binding sites in the promoter region of Ptprj were identified.

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The structure of the 5′-end of the protein-tyrosine phosphatase PTPRJ mRNA reveals a novel mechanism for translation attenuation

Cited by 18 publications

References 31 publications

Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia

Translation of the human erythropoietin transcript is regulated by an upstream open reading frame in response to hypoxia

Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ

Regulated Expression of PTPRJ/CD148 and an Antisense Long Noncoding RNA in Macrophages by Proinflammatory Stimuli

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