MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia.
MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia.
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DOI：
10.1371/journal.pone.0010551
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发表时间：
2010-05-10
期刊：
影响因子：
3.7
通讯作者：
Gao FB
中科院分区：
文献类型：
--
作者：
Jiao J;Herl LD;Farese RV;Gao FB
颗粒蛋白原缺乏被认为会导致某些形式的额颞叶痴呆（FTD），这是一种主要的早发性年龄依赖性神经退行性疾病。颗粒蛋白前体（PGRN）的表达是如何调节的，在很大程度上是未知的。我们在人PGRN（hPGRN）mRNA的3′非翻译区（3′UTR）发现了一个进化上保守的microRNA-29 b（miR-29 b）结合位点。miR-29 b通过hPGRN或小鼠PGRN（mPGRN）3′ UTR下调荧光素酶的表达，而miR-29 b结合位点的突变可使这种下调作用消失。为了检查操纵内源性miR-29 b对hPGRN表达的直接影响，我们建立了一种在巨细胞病毒启动子控制下表达hPGRN的稳定NIH 3 T3细胞系。miR-29 b的异位表达在mRNA和蛋白水平上降低hPGRN表达。相反，用锁核酸敲低内源性miR-29 b增加了NIH 3 T3细胞中hPGRN的产生和分泌。HEK 293细胞中的内源性hPGRN也受miR-29 b调节。这些发现将miR-29 b确定为PGRN表达的新型转录后调节因子，提高了miR-29 b或其他miRNA可能在治疗上靶向增加某些FTD患者的hPGRN水平的可能性。
Progranulin deficiency is thought to cause some forms of frontotemporal dementia (FTD), a major early-onset age-dependent neurodegenerative disease. How progranulin (PGRN) expression is regulated is largely unknown. We identified an evolutionarily conserved binding site for microRNA-29b (miR-29b) in the 3′ untranslated region (3′UTR) of the human PGRN (hPGRN) mRNA. miR-29b downregulates the expression of luciferase through hPGRN or mouse PGRN (mPGRN) 3′UTRs, and the regulation was abolished by mutations in the miR-29b binding site. To examine the direct effect of manipulating endogenous miR-29b on hPGRN expression, we established a stable NIH3T3 cell line that expresses hPGRN under the control of the cytomegalovirus promoter. Ectopic expression of miR-29b decreased hPGRN expression at the both mRNA and protein levels. Conversely, knockdown of endogenous miR-29b with locked nucleic acid increased the production and secretion of hPGRN in NIH3T3 cells. Endogenous hPGRN in HEK 293 cells was also regulated by miR-29b. These findings identify miR-29b as a novel posttranscriptional regulator of PGRN expression, raising the possibility that miR-29b or other miRNAs might be targeted therapeutically to increase hPGRN levels in some FTD patients.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
14.5
作者：
Neumann, Manuela;Rademakers, Rosa;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.