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首页> 外文期刊>Journal of Molecular Biology >Transcriptional activation of the suppressor of cytokine signaling-3 (SOCS-3) gene via STAT3 is increased in F9 REX1 (ZFP-42) knockout teratocarcinoma stem cells relative to wild-type cells
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Transcriptional activation of the suppressor of cytokine signaling-3 (SOCS-3) gene via STAT3 is increased in F9 REX1 (ZFP-42) knockout teratocarcinoma stem cells relative to wild-type cells

机译：与野生型细胞相比，F9 REX1（ZFP-42）敲除畸胎瘤干细胞中通过STAT3抑制细胞因子信号转导3（SOCS-3）基因的转录激活增加。

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摘要

Rex1 (Zfp42), first identified as a gene that is transcriptionally repressed by retinoic acid (RA), encodes a zinc finger transcription factor expressed at high levels in F9 teratocarcinoma stem cells, embryonic stem cells, and other stem cells. Loss of both alleles of Rex1 by homologous recombination alters the RA-induced differentiation of F9 cells, a model of pluripotent embryonic stem cells. We identified Suppressor of Cytokine Signaling-3 (SOCS-3) as a gene that exhibits greatly increased transcriptional activation in RA, cAMP, and theophylline (RACT)-treated F9 Rex1(-/)-cells (similar to 25-fold) as compared to wild-type (WT) cells (similar to 2.5-fold). By promoter deletion, mutation, and transient transfection analyses, we have shown that this transcriptional increase is mediated by the STAT3 DNA-binding elements located between -99 to -60 in the SOCS-3 promoter. Overexpression of STAT3 dominantnegative mutants greatly diminishes this SOCS-3 transcriptional increase in F9 Rex1(-/)-cells. This increase in SOCS-3 transcription is associated with a four-to fivefold higher level of tyrosine-phosphorylated STAT3 in the RACT-treated F9 Rex1(-/)-cells as compared to WT. Dominant-negative Src tyrosine kinase, Jak2, and protein kinase A partially reduce the transcriptional activation of the SOCS 3 gene in RACT-treated F9 Rex1 null cells. In contrast, parathyroid hormone peptide enhances the effect of RA in F9 Rex1(-/-) cells, but not in F9 WT. Thus, Rex1, which is highly expressed in stem cells, inhibits signaling via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, thereby modulating the differentiation of F9 cells. (c) 2007 Elsevier Ltd. All rights reserved.
机译：Rex1（Zfp42）首先被鉴定为被视黄酸（RA）转录抑制的基因，它编码在F9畸胎癌干细胞，胚胎干细胞和其他干细胞中高水平表达的锌指转录因子。 Rex1的两个等位基因通过同源重组的丧失改变了RA诱导的F9细胞（一种多能胚胎干细胞的模型）的分化。我们将细胞因子信号转导抑制因子3（SOCS-3）鉴定为在RA，cAMP和茶碱（RACT）处理的F9 Rex1（-/）细胞（约25倍）中表现出转录激活大大增强的基因，与野生型（WT）细胞相比（约2.5倍）。通过启动子删除，突变和瞬时转染分析，我们已经表明，这种转录增加是由位于SOCS-3启动子中-99至-60之间的STAT3 DNA结合元件介导的。 STAT3显性负突变体的过表达大大减少了F9 Rex1（-/）-细胞中这种SOCS-3转录的增加。与WT相比，RACT处理的F9 Rex1（-/）细胞中SOCS-3转录的这种增加与酪氨酸磷酸化STAT3的四到五倍高水平相关。显性阴性Src酪氨酸激酶，Jak2和蛋白激酶A在RACT处理的F9 Rex1空细胞中部分降低SOCS 3基因的转录激活。相比之下，甲状旁腺激素肽增强RA在F9 Rex1（-/-）细胞中的作用，但在F9 WT中不增强。因此，在干细胞中高度表达的Rex1抑制了通过Janus激酶（JAK）/信号转导子和转录激活子（STAT）通路的信号传导，从而调节F9细胞的分化。 （c）2007 Elsevier Ltd.保留所有权利。

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