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Proteasome Function is Required for Platelet Production

ABSTRACT: RNA-seq expression analysis of transcripts encoding proteasome subunits in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE58202 | GEO | 2015/01/31

SECONDARY ACCESSION(S): PRJNA251563

REPOSITORIES: GEO

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Proteasome Function is Required for Platelet Production

Project description:RNA-seq expression analysis of transcripts encoding proteasome subunits in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes. Analysis of transcript expression in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes.

2015-01-31 | E-GEOD-58202 | biostudies-arrayexpress

Proteasome Function is Required for Platelet Production

Project description:Proteasome Function is Required for Platelet Production

| PRJNA251563 | ENA

Gene expression profiles of cultured megakaryocytes

Project description:Cells obtained from adipose tissue are able to differentiate into megakaryocytes. We compared the gene expression profile of human adipose tissue derived megakaryocytes with that of megakaryocytes differentiated from human CD34 positive cord blood hematopoietic stem cells.

2021-04-05 | GSE112820 | GEO

Proteasome function is required for platelet production.

Project description:The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1(fl/fl) Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-κB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made thrombocytopenic by tamoxifen-induced suppression of proteasome activity in megakaryocytes and platelets (Psmc1(fl/fl) Pdgf-Cre-ER mice). These results indicate that proteasome function is critical for thrombopoiesis, and suggest inhibition of RhoA signaling as a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.

| S-EPMC4151230 | biostudies-literature

Expression of thioredoxin-interacting protein (TXNIP) during megakaryopoiesis is indispensable for platelet biogenesis

Project description:Thioredoxin-interacting protein (TXNIP) is ubiquitously expressed in blood cells, including hematopoietic stem cells (HSCs), monocytes, and platelets. Here we report a novel finding that TXNIP plays a crucial role in megakaryopoiesis and platelet biogenesis via interacting with GATA1, a transcription factor for megakaryocyte-erythroid differentiation. Txnip-/- mice displayed immature megakaryocytes in the bone marrow with thrombocytopenia, which had gotten worse as the mice aged. Transcriptome analysis revealed that the transcriptional activity of GATA1 was significantly enhanced in the Txnip-/- megakaryocyte precursors (MkPs) than wild type (WT) cells. During megakaryopoiesis in ex vivo, Txnip-/- MkPs remained small in cell size with less mitochondrial mass, and more glycolysis for ATP production, as opposed to the normal megakaryocyte maturation. The effects of TXNIP in megakaryocytes were recapitulated in human cord blood CD34+ HSC-derived differentiation. Taken together, this study demonstrates the importance of spatiotemporal expression of TXNIP in platelet biogenesis. We propose for the first time that TXNIP might play a critical role in determining a lineage between megakaryocytes and erythroid cells from a common megakaryocyte-erythroid progenitor via regulation of transcriptional activity of GATA1.

2022-12-31 | GSE186400 | GEO

Acute Megakaryoblast Leukemia LC-MS/MS

Project description:Cord blood CD34 derived megakaryoblasts, cord blood CD34 derived megakaryoblasts gene modified with the CBFA2T3-GLIS2 fusion oncogene, and CBFA2T3-GLIS2 positive acute megakaryoblast leukemia patient samples underwent multiplexed mass spectrometry-based proteomic analysis.

2024-10-10 | PXD048474 | Pride

Effect of HES6 knockdown on gene expression in vitro differentiated megakaryocytes, erythroblasts and precursor cells, cultured from CB CD34+ HSPCs.

Project description:Cord blood CD34+ hematopoietic precursors (3 donors) were control or HES6 shRNA (HES6 knockdown) transduced and cultured for four days in media containing SCF, TPO and EPO to drive differentiation towards megakaryocytes and erythroid cells. After four days four subpopulations were sorted for RNA isolation to research the effect of HES6 knockdown on gene expression. We sorted megakaryocytes (CD41+) and early (CD71+ CD235-) and late (CD71+ CD235+) erythroblasts (CD41-) and CD34- precursor cells (CD41- CD71- CD235- CD34-).

2024-11-13 | GSE229196 | GEO

Tight Junction Protein 1 is a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma

Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.

2015-12-31 | E-GEOD-52369 | biostudies-arrayexpress

siRNA of human MCF7 cells incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity and knocked down for proteosomal subunits

Project description:Reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 are frequently found in many human cancers and correlate directly with patient prognosis. Specifically ubiquitin dependent proteasomal turnover has been shown to cause reduced p27 expression in many human cancers. We recently demonstated that expression of a stabilized version of p27kip1 (p27kip1T187A) in a genetically modified mouse significantly reduced the number of intestinal adenomatous polyps which progressed to invasive carcinomas. Based on this work we set out to identify compounds which lead to a re-expression of p27 in cancer tissues. In this work we identify Argyrin A a compound derived from myxobacterium archangium gephyra as a potent inducer of p27kip1 expression. Argyrin A induces apoptosis in human colon cancer xenografts and tumor vasculature in vivo leading to a profound reduction in tumor size at well tolerated levels. Argyrin A functions are strictly dependent on the expression of p27kip1 as neither tumor cells nor endothelial cells which do not express p27kip1 respond to this compound. Surprisingly the molecular mechanism by which Argyrin A exerts its p27 dependent biological function is through a potent inhibition of the 20S proteasome. Experiment Overall Design: MCF7 cells were incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity was reduced by treatment with siRNA against proteasomal subunits and gene expression profiles were determined at different timepoints thereafter.

2008-06-16 | E-GEOD-8565 | biostudies-arrayexpress

RNA Binding Protein SRSF3 confers an essential role in megakaryocyte maturation and platelet production

Project description:RNA sequencing was performed to identify gene expression changes following SRSF3 depletion in mouse bone marrow megakaryocytes and peripheral blood platelets.

2021-12-21 | GSE155620 | GEO

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