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首页> 外文期刊>Molecular and Cellular Biology >A KLF4–miRNA-206 Autoregulatory Feedback Loop Can Promote or Inhibit Protein Translation Depending upon Cell Context
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A KLF4–miRNA-206 Autoregulatory Feedback Loop Can Promote or Inhibit Protein Translation Depending upon Cell Context

机译：KLF4–miRNA-206自调节反馈环可根据细胞情况促进或抑制蛋白质翻译

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摘要

Krüppel-like factor 4 (KLF4), a transcription factor that regulates cell fate in a context-dependent fashion, is normally induced upon growth arrest or differentiation. In many cancer cells there is dysregulation, with increased expression in proliferating cells. To identify sequence elements that mediate KLF4 suppression in normal epithelial cells, we utilized a luciferase reporter and RK3E cells, which undergo a proliferation-differentiation switch to form an epithelial sheet. A translational control element (TCE) within the KLF4 3′-untranslated region interacted with microRNAs (miRs) 206 and 344-1 to promote or inhibit KLF4 expression, respectively, in proliferating epithelial cells. Overall, the TCE suppressed expression in proliferating primary human mammary epithelial cells, but this suppressive effect was attenuated in immortalized mammary epithelial MCF10A cells, in which Dicer1 and miR-206 promoted KLF4 expression and TCE reporter activity. In contrast to MCF10A cells, in breast cancer cells the activity of miR-206 was switched, and it repressed KLF4 expression and TCE reporter activity. As miR-206 levels were KLF4 dependent, the results identify a KLF4–miR-206 feedback pathway that oppositely affects protein translation in normal cells and cancer cells. In addition, the results indicate that two distinct miRs can have opposite and competing effects on translation in proliferating cells.
机译：Krüppel样因子4（KLF4）是一种转录因子，其以上下文相关的方式调节细胞命运，通常在生长停滞或分化时被诱导。在许多癌细胞中存在失调，在增殖细胞中表达增加。为了鉴定介导正常上皮细胞中KLF4抑制的序列元件，我们利用了萤光素酶报道分子和RK3E细胞，它们经历了增殖-分化转换以形成上皮层。在增生的上皮细胞中，KLF4 3'-非翻译区内的翻译控制元件（TCE）与microRNA（miRs）206和344-1相互作用，分别促进或抑制KLF4表达。总体而言，TCE抑制了增殖的原代人乳腺上皮细胞中的表达，但这种抑制作用在永生化的乳腺上皮MCF10A细胞中减弱了，其中Dicer1和miR-206促进KLF4表达和TCE报告基因活性。与MCF10A细胞相反，在乳腺癌细胞中，miR-206的活性被切换，并且它抑制KLF4表达和TCE报告基因活性。由于miR-206水平是KLF4依赖性的，因此结果确定了一条KLF4–miR-206反馈途径，该途径对正常细胞和癌细胞中的蛋白质翻译产生相反的影响。此外，结果表明，两个不同的miR对增殖细胞中的翻译可能具有相反和竞争的作用。

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