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A novel role of CKIP-1 in promoting megakaryocytic differentiation.

ABSTRACT: Casein kinase 2-interacting protein-1 (CKIP-1) is a known regulator of cardiomyocytes and macrophage proliferation. In this study, we showed that CKIP-1 was involved in the process of megakaryocytic differentiation. During megakaryocytic differentiation of K562 cells, CKIP-1 was dramatically upregulated and this upregulation induced by PMA was mediated through downregulation of transcription factor GATA-1. By transient transfection, oligonucleotide-directed mutagenesis and chromatin immunoprecipitation assays, we identified the transcriptional regulation of CKIP-1 by GATA-1. Overexpression of CKIP-1 initiated events of spontaneous megakaryocytic differentiation in K562 cells. Conversely, knockdown of CKIP-1 in cell lines suppressed megakaryocytic differentiation. Mechanistically, overexpression of CKIP-1 changed the expression levels of transcription factors that have been shown to be critical in erythro-megakaryocytic differentiation such as Fli-1, c-Myb and c-Myc. In vivo analysis confirmed that CKIP-1-/- mice had decreased number of CD41+ cells harvested from bone marrow, and lower platelet levels when compared to wild-type littermates. This is the first direct evidence suggesting that CKIP-1 is a novel regulator of megakaryocytic differentiation.

SUBMITTER: Fan J

PROVIDER: S-EPMC5444732 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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A novel role of CKIP-1 in promoting megakaryocytic differentiation.

Fan Jiao J Wang Yiwu Y Shen Yuan Y Liu Qingyan Q Gao Rong R Qiu Ya Y Wang Chanjuan C Zhang Lingqiang L

Oncotarget 20170501 18

Casein kinase 2-interacting protein-1 (CKIP-1) is a known regulator of cardiomyocytes and macrophage proliferation. In this study, we showed that CKIP-1 was involved in the process of megakaryocytic differentiation. During megakaryocytic differentiation of K562 cells, CKIP-1 was dramatically upregulated and this upregulation induced by PMA was mediated through downregulation of transcription factor GATA-1. By transient transfection, oligonucleotide-directed mutagenesis and chromatin immunoprecip ...[more]

PMID: 28404913

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Project description:BackgroundProper control of the lineage bias of megakaryocytic and erythroid progenitor cells (MEPs) is of significant importance, the disorder of which will lead to abnormalities in the number and function of platelets and erythrocytes. Unfortunately, the signaling pathways regulating MEP differentiation largely remain to be elucidated. This study aimed to analyze the role and the underlying molecular mechanism of miR-1915-3p in megakaryocytic and erythroid differentiation.MethodsWe utilized miRNA mimics and miRNA sponge to alter the expression of miR-1915-3p in megakaryocytic and/or erythroid potential cells; siRNA and overexpression plasmid to change the expression of SOCS4, a potential target of miR-1915-3p. The expression of relevant surface markers was detected by flow cytometry. We scanned for miR-1915-3p target genes by mRNA expression profiling and bioinformatic analysis, and confirmed the targeting by dual-luciferase reporter assay, western blot and gain- and lost-of-function studies. One-way ANOVA and t-test were used to analyze the statistical significance.ResultsIn this study, overexpression or knockdown of miR-1915-3p inhibited or promoted erythroid differentiation, respectively. Accordingly, we scanned for miR-1915-3p target genes and confirmed that SOCS4 is one of the direct targets of miR-1915-3p. An attentive examination of the endogenous expression of SOCS4 during megakaryocytic and erythroid differentiation suggested the involvement of SOCS4 in erythroid/megakaryocytic lineage determination. SOCS4 knockdown lessened erythroid surface markers expression, as well as improved megakaryocytic differentiation, similar to the effects of miR-1915-3p overexpression. While SOCS4 overexpression resulted in reversed effects. SOCS4 overexpression in miR-1915-3p upregulated cells rescued the effect of miR-1915-3p.ConclusionsmiR-1915-3p acts as a negative regulator of erythropoiesis, and positively in thrombopoiesis. SOCS4 is one of the key mediators of miR-1915-3p during the differentiation of MEPs.

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A novel role of CKIP-1 in promoting megakaryocytic differentiation.

Publications

A novel role of CKIP-1 in promoting megakaryocytic differentiation.

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