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首页> 外文期刊>Cellular Physiology and Biochemistry >Small nuclear RNAs U11 and U12 modulate expression of TNR-CFTR mRNA in mammalian kidneys
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Small nuclear RNAs U11 and U12 modulate expression of TNR-CFTR mRNA in mammalian kidneys

机译：小核RNA U11和U12调节哺乳动物肾脏中TNR-CFTR mRNA的表达

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摘要

TNR-CFTR, discovered as a splice variant of CFTR (Cystic Fibrosis Transmembrane conductance Regulator), is distributed in different tissues such as human and rat kidney, trachea, lungs etc and is a functional chloride channel. In Kidneys, our findings show TNR-CFTR to have an unique distribution pattern with low levels of expression in renal cortex and high levels of expression in renal medulla. As shown by us previously, TNR-CFTR mRNA lacks 145 bp corresponding to segments of exons 13 and 14. This deletion causes a frame shift mutation leading to reading of a premature termination codon in exon 14. Premature termination of translation produces a functional half molecule of CFTR; TNR-CFTR. Our analysis of TNR mRNA has shown that the putative alternatively spliced intron has in its 5' and 3' conserved element CT and AC, respectively, that can be recognized by snRNAs U11 and U12. With these findings, we hypothesize that TNR-CFTR mRNA alternative splicing is probably mediate by splicing pathways utilizing U11 and U12 snRNAs. In this study, we have determined sequences of snRNAs U11 and U12 derived from rat kidney, which show significant homology to human U11 and U12 snRNAs. We show that there is significantly lower expression of U11 and U12 snRNAs in renal cortex compared to renal medulla in both humans and rats. This renal pattern of distribution of U11 and U12 snRNAs in both humans and rats closely follows distribution pattern of renal TNR-CFTR. Further, we have shown that blocking U11 and/or U12 mRNAs, by using antisense probes transfected in Immortalized Rat Proximal Tubule Cell line (IRPTC), decreases TNR-CFTR mRNA expression but not wild-type CFTR mRNA expression. Our results suggest that expression of U11 and/or U12 snRNAs is important for non-conventional alternative splicing process that gives rise to mRNA transcript coding for TNR-CFTR.
机译：TNR-CFTR被发现为CFTR（囊性纤维化跨膜电导调节剂）的剪接变体，分布在不同的组织中，例如人和大鼠的肾脏，气管，肺等，并且是功能性的氯离子通道。在肾脏中，我们的发现表明TNR-CFTR具有独特的分布模式，在肾皮质中的表达水平较低，而在肾髓质中的表达水平较高。如我们先前所显示，TNR-CFTR mRNA缺少对应于外显子13和14片段的145 bp。此缺失导致移码突变，导致读取外显子14中的过早终止密码子。翻译的过早终止产生功能性半分子CFTR; TNR-CFTR。我们对TNR mRNA的分析表明，推定的选择性剪接的内含子在其5'和3'保守区分别具有CT和AC保守分子，可以被snRNA U11和U12识别。有了这些发现，我们假设TNR-CFTR mRNA的选择性剪接可能是通过利用U11和U12 snRNA的剪接途径介导的。在这项研究中，我们确定了源自大鼠肾脏的snRNA U11和U12的序列，这些序列与人U11和U12 snRNA表现出显着的同源性。我们显示，在人类和大鼠中，与肾髓质相比，肾皮质中U11和U12 snRNA的表达明显较低。在人和大鼠中，U11和U12 snRNA的这种肾脏分布方式都非常接近肾脏TNR-CFTR的分布方式。此外，我们已经显示，通过使用在永生化大鼠近端肾小管细胞系（IRPTC）中转染的反义探针来阻断U11和/或U12 mRNA，可降低TNR-CFTR mRNA表达，但不会降低野生型CFTR mRNA表达。我们的结果表明，U11和/或U12 snRNA的表达对于非常规的选择性剪接过程非常重要，该过程会产生编码TNR-CFTR的mRNA转录本。

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