An RNA biding protein, Y14 interacts with and modulates STAT3 activation

Ohbayashi, Norihiko; Taira, Naohisa; Kawakami, Shiho; Togi, Sumihito; Sato, Noriko; Ikeda, Osamu; Kamitani, Shinya; Muromoto, Ryuta; Sekine, Yoshifumi; Matsuda, Tadashi

doi:10.1016/j.bbrc.2008.05.073

Cited by 25 publications

(27 citation statements)

References 24 publications

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“…RBM8A encodes Y14, an RNA binding protein that interacts with the C-terminal domain of STAT3 and RNA interference causes its downregulation in Hep3B cells incubated with interleukin-6. 36 Although, we did not observe altered expression in lymphoblastoid cell lines, it remains a candidate gene. Interestingly, TXNIP mRNA expression is increased 8-fold in megakaryocytes compared to in lymphoblastoid cell lines.…”

Section: Discussioncontrasting

confidence: 60%

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

Fiedler

Strauß²,

Wannack³

et al. 2011

Haematologica

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BackgroundThrombocytopenia with absent radii syndrome is defined by bilateral radius aplasia and thrombocytopenia. Due to impaired thrombopoietin signaling there are only few bone marrow megakaryocytes and these are immature; the resulting platelet production defect improves somewhat over time. A microdeletion on chromosome 1q21 is present in all patients but is not sufficient to form thrombocytopenia with absent radii syndrome. We aimed to refine the signaling defect in this syndrome. Design and MethodsWe report an extended study of 23 pediatric and adult patients suffering from thrombocytopenia with absent radii syndrome in order to scrutinize thrombopoietin signal transduction by immunoblotting and gel electrophoretic shift assays. In addition, platelet immunotyping and reactivity were analyzed by flow cytometry. Results were correlated with clinical data including age and platelet counts. ResultsTwo distinct signaling patterns were identified. Juvenile patients showed abrogated thrombopoietin signaling (pattern #1), which is restored in adults (pattern #2). Phosphorylated Jak2 was indicative of activation of STAT1, 3 and 5, Tyk2, ERK, and Akt, showing its pivotal role in distinct thrombopoietin-dependent pathways. Jak2 cDNA was not mutated and the thrombopoietin receptor was present on platelets. All platelets of patients expressed normal levels of CD41/61, CD49b, and CD49f receptors, while CD42a/b and CD29 were slightly reduced and the fibronectin receptor CD49e markedly reduced. Lysosomal granule release in response to thrombin receptor activating peptide was diminished. ConclusionsWe show a combined defect of platelet production and function in thrombocytopenia with absent radii syndrome. The rise in platelets that most patients have during the first years of life preceded the restored thrombopoietin signaling detected at a much later age, implying that these events are uncoupled and that an unknown factor mediates the improvement of platelet production.

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Section: Discussioncontrasting

confidence: 60%

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

Fiedler

Strauß²,

Wannack³

et al. 2011

Haematologica

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“…Expression vectors, STAT3-LUC and STAT3-C were provided by Dr. T. Hirano (Osaka University, Osaka, Japan) and Dr. J. F. Bromberg (Rockefeller Univ., New York, NY), respectively [15,16]. Epitope-tagged Y14 and MAGOH was generated by PCR and sequenced (primer sequences are available upon request) [10].…”

Section: Methodsmentioning

confidence: 99%

“…The complex binds preferentially to spliced mRNAs immediately upstream of exon-junctions, and remains bound to the mRNAs after nuclear export [11,12]. In a previous study, we identified Y14 as a novel binding partner of STAT3 [10]. Y14 binds to STAT3 and affects IL-6-induced STAT3 transactivation by influencing the tyrosine-phosphorylation, nuclear accumulation and DNA-binding activity of STAT3.…”

Section: Introductionmentioning

confidence: 95%

The exon-junction complex proteins, Y14 and MAGOH regulate STAT3 activation

Muromoto¹,

Taira²,

Ikeda³

et al. 2009

Biochemical and Biophysical Research Communications

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Signal transducer and activator of transcription 3 (STAT3), which is activated by cytokines and growth factors, mediates biological actions in many physiological processes. In a previous study, we found that Y14, a core component of the exon-junction complex (EJC) bound to STAT3 and upregulated the transcriptional activity of STAT3 by influencing its DNA-binding activity. In the present study, we demonstrate that STAT3 endogenously interacts with Y14. In addition, we found that MAGOH, a Y14 partner in the EJC, inhibits the STAT3-Y14 complex formation.Furthermore, small-interfering RNA-mediated reduction of MAGOH expression enhanced interleukin-6-induced gene expression. These results indicate that MAGOH regulates the transcriptional activation of STAT3 by interfering complex formation between STAT3 and Y14.

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“…Expression vectors for Y14, TNFR, NF-kB/p65, p50, p100, c-Rel, RIP1, TRADD, TRAF2/5, TAK1, NEMO, IKKa/b, IL-6 promoter-luciferase (pIL-6-LUC), and NF-kB-luciferase (NF-kB-LUC) were kindly provided by J. Inoue (Tokyo University, Tokyo, Japan), T. Kobayashi (Keio University, Tokyo, Japan), T. Fujita (Kyoto University, Kyoto, Japan), S. Akira (Osaka University), and H. Sakurai (Toyama University, Toyama, Japan) (22)(23)(24)(25). Expression vectors for Y14 were described previously (20,21). Anti-Y14, anti-MAGOH, anti-NF-kB/p65, anti-IkBa, anti-STAT3, anti-p300, anti-TRADD, and anti-Myc Abs were obtained from Santa Cruz Biotechnology (Santa Cruz, CA); anti-FLAG, anti-HA Abs were from Sigma-Aldrich (St. Louis, MO); anti-acetyl-NF-kB/p65 (Lys310), anti-pIkBa (Ser 32/36 ), and anti-pSTAT3 (Tyr 705 ) Abs were from Cell Signaling Technology (Beverly, MA); anti-RIP1 and anti-pSTAT3 (Ser 727 ) Abs were from GE Healthcare Life Sciences (Tokyo, Japan); anti-TRAF2 Ab was from AnaSpec (Fremont, CA); and anti-actin Ab was from Millipore (Billerica, MA).…”

Section: Reagents and Absmentioning

confidence: 99%

“…In Drosophila, the Y14-Mago homolog also participates in the transport and translational control of oskar mRNA during oogenesis (17)(18)(19). Although roles for Y14 have been actively examined with regard to mRNA control, we previously found that Y14 binds to a signaling molecule STAT3 (20). Notably, small interfering RNA (siRNA)-mediated reduction of endogenous Y14 expression in a hepatoma cell line (Hep3B) greatly decreased IL-6-induced tyrosine phosphorylation, nuclear accumulation, and DNAbinding activity of STAT3, as well as IL-6/STAT3-dependent gene expression.…”

mentioning

confidence: 99%

Y14 Positively Regulates TNF-α–Induced NF-κB Transcriptional Activity via Interacting RIP1 and TRADD Beyond an Exon Junction Complex Protein

Togi

Shiga

Muromoto

et al. 2013

The Journal of Immunology

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Although Y14 is known to be a component of the exon junction complex, we previously reported that Y14 regulates IL-6–induced STAT3 activation. In this study, we showed that endogenous Y14 positively regulated TNF-α–induced IL-6 expression in HeLa cells. Small interfering RNA–mediated Y14-knockdown reduced TNF-α–induced and NF-κB–mediated transcriptional activity, phosphorylation/degradation of IκBα, and nuclear localization of NF-κB/p65. As in the case of IL-6 stimuli, Y14 enhanced TNF-α–induced STAT3 phosphorylation, which is important for its nuclear retention. However, our manipulation of Y14 expression indicated that it is involved in TNF-α–induced IL-6 expression via both STAT3-dependent and -independent mechanisms. We screened signaling molecules in the TNF-α–NF-κB pathway and found that Y14 endogenously associated with receptor-interacting protein 1 (RIP1) and TNFR-associated death domain (TRADD). Overexpression of RIP1, but not TRADD, restored TNF-α–induced NF-κB activation in Y14-knockdown cells, and Y14 overexpression restored TNF-α–induced NF-κB activation in TRADD-knockdown cells, but not in RIP1-knockdown cells, indicating that Y14 lies downstream of TRADD and upstream of RIP1. Of importance, Y14 significantly enhanced the binding between RIP1 and TRADD, and this is a possible new mechanism for Y14-mediated modification of TNF-α signals. Although Y14 associates with MAGOH in the exon junction complex, Y14’s actions in the TNF-α–NF-κB pathway are unlikely to require MAGOH. Therefore, Y14 positively regulates signals for TNF-α–induced IL-6 production at multiple steps beyond an exon junction complex protein.

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An RNA biding protein, Y14 interacts with and modulates STAT3 activation

Cited by 25 publications

References 24 publications

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

The exon-junction complex proteins, Y14 and MAGOH regulate STAT3 activation

Y14 Positively Regulates TNF-α–Induced NF-κB Transcriptional Activity via Interacting RIP1 and TRADD Beyond an Exon Junction Complex Protein

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