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1.
Biochem Biophys Res Commun ; 552: 142-149, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744762

RESUMO

Fully understanding the regulatory network under the pluripotency of embryonic stem cells (ESC) is a prerequisite for their safe application. Here, we addressed the characteristics of metastasis-associated (MTA) family members in human ESCs and found that knockdown of the expression of MTA2 and MTA3, but not MTA1, would induce differentiation. High-throughput sequence and quantitative real-time PCR showed that the decreased MTA2 or MTA3 gene transcript mainly led to the emergence of mesendoderm associated markers. Finally, based on the chemical small molecule library screening, we observed that addition of ID8, a specific inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), was able to impair the differentiation phenotype induced by MTA2 and MTA3 reduction. Functional assay showed that ID8 could mediate differentiation caused by MTA2 or MTA3 knockdown mainly through inhibition of DYRK4 activity. Therefore, our finding provides the evidence that the functions of MTA family genes in human ESCs are different. Revealing the function of MTA in ESCs with different pluripotency states will help us better understand and apply stem cells.


Assuntos
Diferenciação Celular/genética , Endoderma/metabolismo , Histona Desacetilases/genética , Células-Tronco Embrionárias Humanas/metabolismo , Mesoderma/metabolismo , Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Animais , Linhagem Celular , Endoderma/citologia , Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Humanos , Mesoderma/citologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Interferência de RNA , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Quinases Dyrk
2.
Aging (Albany NY) ; 13(6): 9011-9027, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33759814

RESUMO

Protein inhibitor of activated STAT1 (PIAS1), a small ubiquitin-like modifier (SUMO) E3 ligase, was considered to be an inhibitor of STAT1 by inhibiting the DNA-binding activity of STAT1 and blocking STAT1-mediated gene transcription in response to cytokine stimulation. PIAS1 has been determined to be involved in modulating several biological processes such as cell proliferation, DNA damage responses, and inflammatory responses, both in vivo and in vitro. However, the role played by PIAS1 in regulating neurodegenerative diseases, including Alzheimer's disease (AD), has not been determined. In our study, significantly different expression levels of PIAS1 between normal controls and AD patients were detected in four regions of the human brain. Based on a functional analysis of Pias1 in undifferentiated mouse hippocampal neuronal HT-22 cells, we observed that the expression levels of several AD marker genes could be inhibited by Pias1 overexpression. Moreover, the proliferation ability of HT-22 cells could be promoted by the overexpression of Pias1. Furthermore, we performed RNA sequencing (RNA-seq) to evaluate and quantify the gene expression profiles in response to Pias1 overexpression in HT-22 cells. As a result, 285 significantly dysregulated genes, including 79 upregulated genes and 206 downregulated genes, were identified by the comparison of Pias1/+ cells with WT cells. Among these genes, five overlapping genes, including early growth response 1 (Egr1), early growth response 2 (Egr2), early growth response 3 (Egr3), FBJ osteosarcoma oncogene (Fos) and fos-like antigen 1 (Fosl1), were identified by comparison of the transcription factor binding site (TFBS) prediction results for STAT1, whose expression was evaluated by qPCR. Three cell cycle inhibitors, p53, p18 and p21, were significantly downregulated with the overexpression of Pias1. Analysis of functional enrichment and expression levels showed that basic region leucine zipper domain-containing transcription factors including zinc finger C2H2 (zf-C2H2), homeobox and basic/helix-loop-helix (bHLH) in several signaling pathways were significantly involved in PIAS1 regulation in HT-22 cells. A reconstructed regulatory network under PIAS1 overexpression demonstrated that there were 43 related proteins, notably Nr3c2, that directly interacted with PIAS1.


Assuntos
Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Animais , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Humanos , Camundongos , Proteínas Inibidoras de STAT Ativados/genética , Análise de Sequência de RNA
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