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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >REDUCTION OF INSULIN GENE TRANSCRIPTION IN HIT-T15 BETA CELLS CHRONICALLY EXPOSED TO A SUPRAPHYSIOLOGIC GLUCOSE CONCENTRATION IS ASSOCIATED WITH LOSS OF STF-1 TRANSCRIPTION FACTOR EXPRESSION
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REDUCTION OF INSULIN GENE TRANSCRIPTION IN HIT-T15 BETA CELLS CHRONICALLY EXPOSED TO A SUPRAPHYSIOLOGIC GLUCOSE CONCENTRATION IS ASSOCIATED WITH LOSS OF STF-1 TRANSCRIPTION FACTOR EXPRESSION

机译：STF-1转录因子表达的损失与长期暴露于超生理性葡萄糖浓度的HIT-T15 BETA细胞中胰岛素基因转录的减少有关

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Chronic exposure of HIT-T15 beta cells to elevated glucose concentrations leads to decreased insulin gene transcription, The reduction in expression is accompanied by diminished binding of a glucose sensitive transcription factor (termed GSTF) that interacts with two (A+T)-rich elements within the 5' flanking control region of the insulin gene, In this study we examined whether GSTF corresponds to the recently cloned insulin gene transcription factor STF-1, a homeodomain protein whose expression is restricted to the nucleus of endodermal cells of the duodenum and pancreas, We found that an affinity-purified antibody recognizing STF-1 supershifted the GSTF activator complex formed from HIT-T15 extracts, In addition, we demonstrated a reduction in STF-1 mRNA and protein levels that closely correlated with the change in GSTF binding in HIT-T15 cells chronically cultured under supraphysiologic glucose concentrations. The reduction in STF-1 expression in these cells could be accounted for by a change in the rate of STF-1 gene transcription, suggesting a posttranscriptional control mechanism, In support of this hypothesis, no STF-1 mRNA accumulated in HIT-T15 cells passaged in 11.1 mM glucose. The only RNA species detected was a 6.4-kb STF-1 RNA species that hybridized with 5' and 3' STF-1-specific cDNA probes. We suggest that the 6.4-kb RNA represents an STF-1 mRNA precursor and that splicing of this RNA is defective in these cells, Overall, this study suggests that reduced expression of a key transcriptional regulatory factor, STF-1, contributes to the decrease in insulin gene transcription in HIT-T15 cells chronically cultured in supraphysiologic glucose concentration. [References: 43]
机译：HIT-T15β细胞长期暴露于升高的葡萄糖浓度下会导致胰岛素基因转录降低。表达的降低伴随着与两个富含（A + T）元素相互作用的葡萄糖敏感性转录因子（称为GSTF）的结合减少在胰岛素基因的5'侧翼控制区域内，在这项研究中，我们检查了GSTF是否对应于最近克隆的胰岛素基因转录因子STF-1，这是一个同源域蛋白，其表达局限于十二指肠和胰腺内胚层细胞核，我们发现识别STF-1的亲和纯化抗体使由HIT-T15提取物形成的GSTF激活剂复合物超移。此外，我们证明了STF-1 mRNA和蛋白质水平的降低与GSTF结合变化密切相关。在超生理葡萄糖浓度下长期培养的HIT-T15细胞。这些细胞中STF-1表达的减少可能是由于STF-1基因转录速率的变化所致，提示转录后控制机制。为支持这一假设，HIT-T15细胞中未积累STF-1 mRNA在11.1 mM葡萄糖中传代。检测到的唯一RNA种类是与5'和3'STF-1特异性cDNA探针杂交的6.4-kb STF-1 RNA种类。我们建议6.4-kb RNA代表STF-1 mRNA的前体，并且该RNA的剪接在这些细胞中是有缺陷的。总的来说，这项研究表明关键转录调节因子STF-1的表达减少有助于减少超生理葡萄糖浓度长期培养的HIT-T15细胞中胰岛素基因转录水平的变化。 [参考：43]

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