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Destabilization of Nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fiber formation

ABSTRACT: HuR promotes myogenesis by stabilizing MyoD, Myogenin and p21 mRNAs during the fusion step of muscle cells to form myotubes. Here we show that HuR, via a novel mRNA destabilizing activity, promotes the early steps of myogenesis by reducing the expression of the cell cycle promoter nucleophosmin (NPM). Depletion of HuR stabilizes the NPM mRNA, increases NPM protein levels and inhibits myogenesis, while its overexpression elicits the opposite effects. NPM mRNA destabilization involves the association of HuR with the decay factor KSRP as well as the ribonuclease PARN and the exosome complex. The C-terminus of HuR mediates the formation of the HuR-KSRP complex and is sufficient for maintaining a low level of the NPM mRNA as well as promoting the commitment of muscle cells to myogenesis. We therefore propose a model whereby the downregulation of the NPM mRNA, mediated by the HuR/KSRP complex and its associated ribonucleases, is required for proper myogenesis.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE57113 | GEO | 2014/04/26

SECONDARY ACCESSION(S): PRJNA245448

REPOSITORIES: GEO

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Destabilization of Nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fiber formation

Project description:HuR promotes myogenesis by stabilizing MyoD, Myogenin and p21 mRNAs during the fusion step of muscle cells to form myotubes. Here we show that HuR, via a novel mRNA destabilizing activity, promotes the early steps of myogenesis by reducing the expression of the cell cycle promoter nucleophosmin (NPM). Depletion of HuR stabilizes the NPM mRNA, increases NPM protein levels and inhibits myogenesis, while its overexpression elicits the opposite effects. NPM mRNA destabilization involves the association of HuR with the decay factor KSRP as well as the ribonuclease PARN and the exosome complex. The C-terminus of HuR mediates the formation of the HuR-KSRP complex and is sufficient for maintaining a low level of the NPM mRNA as well as promoting the commitment of muscle cells to myogenesis. We therefore propose a model whereby the downregulation of the NPM mRNA, mediated by the HuR/KSRP complex and its associated ribonucleases, is required for proper myogenesis. RNA was extracted from C2C12 treated with siRNA against HuR and compared to control siRNA

2014-04-26 | E-GEOD-57113 | biostudies-arrayexpress

Mus musculus

Project description:Destabilization of Nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fiber formation

| PRJNA245448 | ENA

RNA binding protein KSRP mediated miRNAs processing reciprocally regulates granulocytic and monocytic differentiation

Project description:KSRP is involved in RNA processing at multiple levels including alternative splicing, mRNA stability, mRNA localization and translation efficiency. Dysregulation KSRP can cause to hematological malignancies. However, the direct contribution of KSRP to myeloid lineage differentiation is poorly understood. KSRP, as a KH-type splicing regulatory protein, which interacts with single-stand AU-rich element containing mRNA and mediated mRNA decay, also serves as a component of Drosha and Dicer complexes and regulates the biogenesis of miRNAs. Whether KSRP mediated miRNAs maturation participated in myeloid lineage differentiation is unknown. Here, we analysis the miRNAs processing during over-expression KSRP in THP-1 cells by poly-A(riched) RNA-seq and miRNA-Seq. Our results suggest that KSRP regulate a class of miRNAs maturation and have a critical function in myeloid lineage differentiation.

2017-08-01 | GSE87318 | GEO

The mRNA-binding protein KSRP limits the inflammatory response of macrophages

Project description:KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the 3´-untranslated region of mRNA species, which in many cases encode dynamically regulated proteins like cytokines. In the present study, we investigated the role of KSRP for the immunophenotype of macrophages using bone marrow-derived macrophages (BMDM) from wild type (WT) and KSRP-/- mice. RNA sequencing revealed that KSRP-/- BMDM displayed significantly higher mRNA expression levels of genes in-volved in inflammatory and immune responses, particularly type I interferon responses, following LPS stimulation. In line, time kinetics studies revealed increased levels of interferon-γ (IFN-γ), in-terleukin (IL)-1β and IL-6 mRNA in KSRP-/- macrophages after 6 h subsequent to LPS stimulation as compared to WT cultures. On protein level KSRP-/- BMDM displayed higher levels of these cy-tokines after overnight stimulation. Matching results were observed for primary peritoneal mac-rophages of KSRP−/− mice. These showed higher IL-6, Tumor necrosis factor-α (TNF-α), C-X-C mo-tif chemokine 1 (CXCL1) and CC-chemokine ligand 5 (CCL5) protein levels in response to LPS stimulation than the WT controls. As macrophages play a key role in sepsis, the in vivo relevance of KSRP deficiency for cytokine/chemokine production was analyzed in an acute inflammation model. In agreement with our in vitro findings, KSRP-deficient animals showed higher cytokine production upon LPS administration in comparison to WT mice. Taken together, these findings demonstrate that KSRP constitutes as an important negative regulator of cytokine expression in macrophages

2024-04-12 | GSE261444 | GEO

KSRP-mediated Transcriptome reshaping

Project description:KSRP knock-down and BMP2 treatment produce a largely overlapping reshape of the transcriptome in C2C12 cells. microRNAs (miRNAs) are essential regulators of development, physiology, and evolution with miRNA biogenesis being strictly controlled at multiple levels. Regulatory proteins, such as KH-type splicing regulatory protein (KSRP), modulate rates and timing of the enzymatic reactions responsible for maturation of select miRNAs from their primary transcripts in response to specific stimuli. Induction of myogenic miRNAs (myomiRs) is essential for muscle differentiation with KSRP phosphorylation being required to convey myogenic signals to enhanced myomiR maturation. Here we show that either KSRP silencing or Bone Morphogenetic Protein (BMP)2-signaling activation in mesenchimal C2C12 cells prevented myogenic differentiation while induced osteoblastic differentiation as revealed by the reshaping of the whole transcriptome analyzed by RNA deep-sequencing. The most striking feature common to both BMP2 signaling activation and KSRP silencing was a blockade of myomiR maturation. Our results demonstrate that phosphorylated SMAD proteins, the transducers of BMP signaling, associate with KSRP and block its interaction with primary-myomiRs. This, in turn, abrogates KSRP-dependent myomiR maturation with the knock-down of SMAD4, 5, and 9 being able to rescue KSRP function. SMAD-induced blockade of KSRP-dependent myomiR maturation, in parallel to the well known SMAD function on gene transcription, inhibits C2C12 cell differentiation into myofibers and contributes to orient cells towards osteoblast lineage. We propose that remodeling of co-regulatory complexes affecting primary-miRNA processing is a mechanism well suited to guide cell fate determination in eukaryotes.

2013-06-25 | GSE38907 | GEO

KSRP-mediated Transcriptome reshaping

2013-06-25 | E-GEOD-38907 | biostudies-arrayexpress

Expression data from KSRP knockdown lung cancer cell

Project description:KSRP depleted CL1-0 cells were used to identify genes regulated by KSRP We used microarrays to detail the global programme of gene expression underlying metastasis and identified distinct classes of KSRP-regulated genes during this process.

2017-07-26 | GSE101842 | GEO

Expression data from KSRP overexpression and knockdown lung cancer cell

2016-06-16 | GSE83388 | GEO

Expression data from KSRP overexpression and knockdown lung cancer cell

Project description:KSRP overexpressed CL1-0 cells and KSRP depleted CL1-5 cells were used to identify genes regulated by KSRP We used microarrays to detail the global programme of gene expression underlying metastasis and identified distinct classes of KSRP-regulated genes during this process. CL1-0 cells stablely depleted KSRP expressing and CL1-5 cells stably expressed KSRP-specific shRNA were analyzed compare to respective control cells

2016-06-16 | E-GEOD-83388 | biostudies-arrayexpress

HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA (miRNA)

Project description:Upon muscle injury the high mobility group box 1 (HMGB1) protein is up-regulated and secreted to initiate reparative responses. Here we show that HMGB1 controls myogenesis both in vitro and in vivo, during development and after adult muscle injury. HMGB1 expression in muscle cells is regulated at the translational level: the miRNA miR-1192 inhibits HMGB1 translation and the RNA-binding protein HuR promotes it. HuR binds to a cis-element, HuRBS, located in the 3'UTR of the HMGB1 transcript, and at the same time miR-1192 is recruited to an adjacent seed element. The binding of HuR to the HuRBS prevents the recruitment of Argonaute 2 (Ago2), overriding miR-1192-mediated translation inhibition. Depleting HuR reduces myoblast fusion and silencing miR-1192 re-establishes the fusion potential of HuR-depleted cells. We propose that HuR promotes the commitment of myoblasts to myogenesis by enhancing the translation of HMGB1 and suppressing the translation inhibition mediated by miR-1192. RNA content was extracted following immunoprecipitation of HuR using a monoclonal antibody (3A2) and the levels of mRNA were compared to an IgG control in order to determine which transcripts were enriched in the HuR ribonucleoprotein complex.

2013-08-14 | E-GEOD-49855 | biostudies-arrayexpress

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