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Tissue Type-Specific Expression of the dsRNA-Binding Protein 76 and Genome-wide Elucidation of its Target mRNAs

ABSTRACT: RNA-binding proteins accompany all steps in the life of mRNAs and provide dynamic gene regulation functions for rapid adjustment to changing extra- or intracellular conditions. The association of RNA-binding proteins with their targets is regulated through changing sub-cellular distribution, post-translational modification or association with other proteins. Tissue type-specific isoform distribution and target mRNA binding patterns are major determinants of post-transcriptional gene regulation by RNA-binding proteins.We demonstrate that the dsRNA binding protein 76 (DRBP76), synonymous with nuclear factor 90, displays inherently distinct tissue type-specific sub-cellular distribution in the normal human central nervous system and in malignant brain tumors of glial origin. Altered sub-cellular localization and isoform distribution in malignant glioma indicate that tumor-specific changes in DRBP76-related gene products and their regulatory functions may contribute to the formation and/or maintenance of these tumors. To identify endogenous mRNA targets of DRBP76, we performed RNA-immunoprecipitation and genome-wide microarray analyses in HEK293 cells, and identified specific classes of transcripts encoding critical functions in cellular metabolism. Our data suggest that DRBP76 expression, isoform distribution and sub-cellular localization are profoundly disturbed upon malignant transformation in the CNS. Thus, DRBP76’s roles in co- or post-transcriptional gene regulation may contribute to the neoplastic phenotype. Keyword: RIP-chip

ORGANISM(S): Homo sapiens

PROVIDER: GSE20001 | GEO | 2010/05/04

SECONDARY ACCESSION(S): PRJNA124069

REPOSITORIES: GEO

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Project description:Boehm2014 - isoform-specific dimerization of pSTAT5A and pSTAT5B To study STAT5 activation, the authors build a dynamic model of pSTAT5 isoform dimerization. Combinatorial binding of pSTAT5A and pSTAT5B is analysed using model hypotheses and concurrent experiments. Model parameters are derived from the experiments on Ba/F3 cells. Results show that pSTAT5 heterodimerization hypothesis for STAT5 activation favours experimental results. This model is described in the article: Identification of isoform-specific dynamics in phosphorylation-dependent STAT5 dimerization by quantitative mass spectrometry and mathematical modeling Boehm ME, Adlung L, Schilling M, Roth S, Klingmüller U, Lehmann WD J Proteome Res. 2014 Dec 5;13(12):5685-94 Abstract: STAT5A and STAT5B are important transcription factors that dimerize and transduce activation signals of cytokine receptors directly to the nucleus. A typical cytokine that mediates STAT5 activation is erythropoietin (Epo). Differential functions of STAT5A and STAT5B have been reported. However, the extent to which phosphorylated STAT5A and STAT5B (pSTAT5A, pSTAT5B) form homo- or heterodimers is not understood, nor is how this might influence the signal transmission to the nucleus. To study this, we designed a concept to investigate the isoform-specific dimerization behavior of pSTAT5A and pSTAT5B that comprises isoform-specific immunoprecipitation (IP), measurement of the degree of phosphorylation, and isoform ratio determination between STAT5A and STAT5B. For the main analytical method, we employed quantitative label-free and -based mass spectrometry. For the cellular model system, we used Epo receptor (EpoR)-expressing BaF3 cells (BaF3-EpoR) stimulated with Epo. Three hypotheses of dimer formation between pSTAT5A and pSTAT5B were used to explain the analytical results by a static mathematical model: formation of (i) homodimers only, (ii) heterodimers only, and (iii) random formation of homo- and heterodimers. The best agreement between experimental data and model simulations was found for the last case. Dynamics of cytoplasmic STAT5 dimerization could be explained by distinct nuclear import rates and individual nuclear retention for homo- and heterodimers of phosphorylated STAT5. This model is hosted on BioModels Database and identified by: BIOMD0000000591. To cite BioModels Database, please use: BioModels: Content, Features, Functionality, and Use.. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Tissue Type-Specific Expression of the dsRNA-Binding Protein 76 and Genome-wide Elucidation of its Target mRNAs

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