Repression of human activation induced cytidine deaminase by miR-93 and miR-155.
Repression of human activation induced cytidine deaminase by miR-93 and miR-155.
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DOI：
10.1186/1471-2407-11-347
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发表时间：
2011-08-10
期刊：
影响因子：
3.8
通讯作者：
Larson ED
中科院分区：
文献类型：
--
作者：
Borchert GM;Holton NW;Larson ED
激活诱导胞苷脱氨酶（AID）靶向活化B细胞的免疫球蛋白基因，将胞苷转化为尿嘧啶，诱导突变和重组。虽然对免疫球蛋白基因多样化至关重要，但AID调控不当可能导致基因组不稳定和致癌转化。这在伯基特淋巴瘤中得到了典型的说明，其特征是艾滋病诱导的c-MYC癌基因与IgH位点的突变和相互易位。最初被认为是B细胞特异性的，AID现在似乎在几种上皮性癌症中错误表达，这增加了AID也可能参与非B细胞癌变的可能性。AID的致突变潜能证明存在能够抑制不适当AID表达的细胞调节因子。MicroRNAs （miRs）具有这种能力，我们已经检查了公开可用的人类AID EST数据集，以寻找miR与人类AID 3'UTR的互补性。在这项工作中，我们评估了两个候选miRs在MCF-7乳腺癌细胞中抑制人类AID表达的能力。我们已经在人类AID mRNA中发现了中等程度的miR-155和明显的miR-93互补靶点。荧光素酶报告基因检测表明，miR-93和miR-155都可以与AID的3'UTR相互作用以阻断表达。此外，MCF-7细胞中miR的过表达会降低内源性AID蛋白，但不会降低mRNA水平。同样表明了AID的翻译调节，MCF-7细胞中miR的缺失会增加AID蛋白水平，而不会同时增加AID mRNA。总之，我们的研究结果表明，miR-93和miR-155组成性地抑制MCF-7细胞中的AID翻译，这表明这些mir在防止基因组胞苷脱氨、突变和致癌转化方面具有广泛的作用。此外，我们对位于AID 3'UTR内的模糊miR-93靶点的表征支持了最近的建议，即由于截断3'UTR注释的普遍存在，许多miR调控被忽视了。
Activation Induced cytidine Deaminase (AID) targets the immunoglobulin genes of activated B cells, where it converts cytidine to uracil to induce mutagenesis and recombination. While essential for immunoglobulin gene diversification, AID misregulation can result in genomic instability and oncogenic transformation. This is classically illustrated in Burkitt's lymphoma, which is characterized by AID-induced mutation and reciprocal translocation of the c-MYC oncogene with the IgH loci. Originally thought to be B cell-specific, AID now appears to be misexpressed in several epithelial cancers, raising the specter that AID may also participate in non-B cell carcinogenesis. The mutagenic potential of AID argues for the existence of cellular regulators capable of repressing inappropriate AID expression. MicroRNAs (miRs) have this capacity, and we have examined the publically available human AID EST dataset for miR complementarities to the human AID 3'UTR. In this work, we have evaluated the capacity of two candidate miRs to repress human AID expression in MCF-7 breast carcinoma cells. We have discovered moderate miR-155 and pronounced miR-93 complementary target sites encoded within the human AID mRNA. Luciferase reporter assays indicate that both miR-93 and miR-155 can interact with the 3'UTR of AID to block expression. In addition, over-expression of either miR in MCF-7 cells reduces endogenous AID protein, but not mRNA, levels. Similarly indicative of AID translational regulation, depletion of either miR in MCF-7 cells increases AID protein levels without concurrent increases in AID mRNA. Together, our findings demonstrate that miR-93 and miR-155 constitutively suppress AID translation in MCF-7 cells, suggesting widespread roles for these miRs in preventing genome cytidine deaminations, mutagenesis, and oncogenic transformation. In addition, our characterization of an obscured miR-93 target site located within the AID 3'UTR supports the recent suggestion that many miR regulations have been overlooked due to the prevalence of truncated 3'UTR annotations.
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影响因子：
3.5
作者：
Borchert GM;Gilmore BL;Spengler RM;Xing Y;Lanier W;Bhattacharya D;Davidson BL
通讯作者：
Davidson BL
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