Cell-specific post-transcriptional regulation of γ-synuclein gene by micro-RNAs.
Cell-specific post-transcriptional regulation of γ-synuclein gene by micro-RNAs.
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细胞特异性后通过微RNA对γ-核蛋白基因的转录调节。
DOI：
10.1371/journal.pone.0073786
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Surguchov A
中科院分区：
文献类型：
--
作者：
Surgucheva I;Gunewardena S;Rao HS;Surguchov A
γ-突触核蛋白是小蛋白突触核蛋白家族的成员，其由三个成员组成：α，β-和γ-突触核蛋白。γ-突触核蛋白在高百分比的晚期和转移性肿瘤中异常表达，但在正常或良性组织中不表达。此外，γ-突触核蛋白的表达与疾病进展密切相关，并且可以刺激癌细胞的增殖，诱导癌细胞的侵袭和转移。γ-突触核蛋白的转录基本上通过AP-1与内含子1中的特定序列的结合来调节。我们发现γ-synuclein的表达也可能在转录后水平受到microRNAs（miRs）的调控。根据多种方法预测，γ-synuclein基因的3′-非翻译区（UTR）含有miRs的靶点。将γ-突触核蛋白3′-UTR插入报告荧光素酶（LUC）基因下游，在转染到SKBR 3和Y 79细胞中后，导致LUC活性降低51%，证实了该片段中存在miR的有效靶标。miR-4437和miR-4674的表达（预测3′-UTR中的推定靶点）导致内源性γ-突触核蛋白表达降低61.2%和60.1%，证实了它们在基因表达调控中的作用。另一方面，在过表达γ-突触核蛋白的细胞中，未发现miR对γ-突触核蛋白表达的显著影响，表明miR仅在低或中等水平的γ-突触核蛋白表达下发挥其调节作用，而在高水平的γ-突触核蛋白表达下不发挥其调节作用。升高的γ-突触核蛋白水平差异性地改变几种miR表达的水平，上调一些miR的水平并下调其他miR的水平。γ-突触核蛋白过表达导致三种miR上调，即，miR-885- 3 p、miR-138和miR-497在γ-synuclein基因的3′-UTR中具有推定的靶点。γ-synuclein差异调节的miRs可能调控信号通路和肿瘤相关基因的表达。这项研究表明，miR可能提供γ-突触核蛋白表达的细胞特异性调节，并为进一步评估其在病理生理过程中的作用奠定了基础。
γ-Synuclein is a member of the synucleins family of small proteins, which consists of three members:α, β- and γ-synuclein. γ-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, γ-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells. γ-Synuclein transcription is regulated basically through the binding of AP-1 to specific sequences in intron 1. Here we show that γ-synuclein expression may be also regulated by micro RNAs (miRs) on post-transcriptional level. According to prediction by several methods, the 3′-untranslated region (UTR) of γ-synuclein gene contains targets for miRs. Insertion of γ-synuclein 3′-UTR downstream of the reporter luciferase (LUC) gene causes a 51% reduction of LUC activity after transfection into SKBR3 and Y79 cells, confirming the presence of efficient targets for miRs in this fragment. Expression of miR-4437 and miR-4674 for which putative targets in 3′-UTR were predicted caused a 61.2% and 60.1% reduction of endogenous γ-synuclein expression confirming their role in gene expression regulation. On the other hand, in cells overexpressing γ-synuclein no significant effect of miRs on γ-synuclein expression was found suggesting that miRs exert their regulatory effect only at low or moderate, but not at high level of γ-synuclein expression. Elevated level of γ-synuclein differentially changes the level of several miRs expression, upregulating the level of some miRs and downregulating the level of others. Three miRs upregulated as a result of γ-synuclein overexpression, i.e., miR-885-3p, miR-138 and miR-497 have putative targets in 3′-UTR of the γ-synuclein gene. Some of miRs differentially regulated by γ-synuclein may modulate signaling pathways and cancer related gene expression. This study demonstrates that miRs might provide cell-specific regulation of γ-synuclein expression and set the stage to further evaluate their role in pathophysiological processes.
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影响因子：
3.7
作者：
Garzia L;Andolfo I;Cusanelli E;Marino N;Petrosino G;De Martino D;Esposito V;Galeone A;Navas L;Esposito S;Gargiulo S;Fattet S;Donofrio V;Cinalli G;Brunetti A;Vecchio LD;Northcott PA;Delattre O;Taylor MD;Iolascon A;Zollo M
通讯作者：
Zollo M
影响因子：
5.6
作者：
Finnerty JR;Wang WX;Hébert SS;Wilfred BR;Mao G;Nelson PT
通讯作者：
Nelson PT
影响因子：
11.2
作者：
Hurst DR;Edmonds MD;Scott GK;Benz CC;Vaidya KS;Welch DR
通讯作者：
Welch DR
影响因子：
6
作者：
Galvin, JE;Giasson, B;Trojanowski, JQ
通讯作者：
Trojanowski, JQ
影响因子：
11.2
作者：
Chen, Hsin-Yi;Lin, Yu-Min;Chen, Ruey-Hwa
通讯作者：
Chen, Ruey-Hwa