Alternative polyadenylation and miR-34 family members regulate tau expression.
Alternative polyadenylation and miR-34 family members regulate tau expression.
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DOI：
10.1111/jnc.12437
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发表时间：
2013-12
影响因子：
4.7
通讯作者：
Wolfe MS
中科院分区：
文献类型：
--
作者：
Dickson JR;Kruse C;Montagna DR;Finsen B;Wolfe MS
Tau在阿尔茨海默病中病理性聚集，并且有证据表明减少Tau表达对于预防或治疗这种疾病可能是安全和有益的。我们试图研究人tau mRNA的3 '-非翻译区（3'-UTR）在调节tau表达中的作用。Tau表达两种3 '-UTR同种型，长型和短型，作为交替多腺苷酸化的结果。使用荧光素酶报告基因构建体，我们发现，这些亚型的表达在人神经母细胞瘤细胞系M17 D和SH-SY 5 Y中受到差异控制。通过计算鉴定了几种微RNA作为可能结合长而非短的tau 3 '-UTR同种型的候选物。随后显示，来自候选物筛选的命中物miR-34 a抑制M17 D细胞中内源性tau蛋白的表达。相反，抑制内源性表达的miR-34家族成员导致内源性tau表达增加。此外，通过使用荧光素酶报告基因测定对人tau 3 '-UTR片段进行无偏筛选，我们鉴定了长tau 3'-UTR同种型中含有调控顺式元件的几个其他区域。通过其3 '-UTR调节tau表达的更好理解可能最终导致开发用于治疗阿尔茨海默病和其他tau蛋白病的新治疗策略。
Tau pathologically aggregates in Alzheimer’s disease, and evidence suggests that reducing tau expression may be safe and beneficial for the prevention or treatment of this disease. We sought to examine the role of the 3’-untranslated region (3’-UTR) of human tau mRNA in regulating tau expression. Tau expresses two 3’-UTR isoforms, long and short, as a result of alternative polyadenylation. Using luciferase reporter constructs, we found that expression from these isoforms is differentially controlled in human neuroblastoma cell lines M17D and SH-SY5Y. Several microRNAs were computationally identified as candidates that might bind the long, but not short, tau 3’-UTR isoform. A hit from a screen of candidates, miR-34a, was subsequently shown to repress the expression of endogenous tau protein in M17D cells. Conversely, inhibition of endogenously expressed miR-34 family members leads to increased endogenous tau expression. Additionally, through an unbiased screen of fragments of the human tau 3’-UTR using a luciferase reporter assay, we identified several other regions in the long tau 3’-UTR isoform that contain regulatory cis-elements. Improved understanding of the regulation of tau expression by its 3’-UTR may ultimately lead to the development of novel therapeutic strategies for the treatment of Alzheimer’s disease and other tauopathies.
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DOI：
10.1073/pnas.85.11.4051
发表时间：
1988-06-01
影响因子：
11.1
作者：
GOEDERT, M;WISCHIK, CM;KLUG, A
通讯作者：
KLUG, A
影响因子：
4.2
作者：
Atlas, Roee;Behar, Leah;Ginzburg, Irith
通讯作者：
Ginzburg, Irith
通过未翻译基因区域和其他非编码元件调节真核基因表达。
影响因子：
8
作者：
Barrett, Lucy W.;Fletcher, Sue;Wilton, Steve D.
通讯作者：
Wilton, Steve D.
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
DOI：
10.1016/0736-5748(95)00001-w
发表时间：
1995-04-01
影响因子：
1.8
作者：
BEHAR, L;MARX, R;GINZBURG, I
通讯作者：
GINZBURG, I