《Cell》亮点 microRNA作用新模式

　　

生物通报道，俄亥俄州立大学免疫与遗传医学系，人类癌症基因组研究中心，RNA生物研究中心以及澳大利亚，丹麦等处的研究者在microRNA作用模式研究方面取得最新的进展，相关成果文章miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts公布在最新一期的Cell上，并被列为本期Cell亮点。

 

文章通讯作者是来自俄亥俄州立大学的Danilo Perrotti博士，目前任助理教授一职，主要从事分子病毒学、免疫学和遗传医学方面的研究。

 

MicroRNAs（miRNAs）是一种小的内源性非编码RNA分子，大约由21－25个核苷酸组成。这些小的miRNA通常靶向一个或者多个mRNA，通过翻译水平的抑制或断裂靶标mRNAs而调节基因的表达。microRNA与异质性核糖蛋白（heterogeneous ribonucleoproteins ，hnRNPs)具有类似的转录后基因调控功能。异质性胞核核糖核蛋白 (hnRNPs)是mRNA成熟加工过程中重要的核酸结合蛋白。

 

在本研究中，科学家们发现，慢性粒细胞白血病原始细胞危象期内一种microRNA，miR-328显著缺失，并且激酶依赖性的MAPK1-hnRNP E2路径被激活。

 

如果重新表达miR-328将及时挽救危象，通过poly（rC）-binding Protein hnRNP E2翻译调节以及mRNA编码激活PIM1促使粒细胞分化。

 

这个相互作用的过程并不依赖MicroRNA的seed sequence，并且会激发CEBPA mRNA的释放。这些结果表明，microRNA具有控制细胞命运的双重路径和功效，它不仅通过mRNA来发挥作用，还通过调节蛋白来发挥作用。

 

microRNA作用模式

miRNAs起源于内源性表达转录本，是长约21-25nt的双链RNA分子，其典型特征是具有发卡结构。图1表述了对当前miRNA和siRNA起源的理解。miRNA途径开始于一个miRNA基因的pri-miRNA（PrimarymiRNA）转录本（step 1）；这个70－100nt的发卡RNAs（pri-miRNA）在核内被核糖核酸酶Drosha加工处理而最终成为pre-miRNA（Precursor miRNA，）（step 2）；之后pre-miRNA被核输出蛋白exportin 5转运入胞质（step 3），接着被第二个核糖核酸酶Dicer消化为21－25nt的miRNA（step 4）；这个阶段的miRNA可以结合RISC（RNA-Induced Silencing Complex）并与靶标mRNA互补并列（step5－6）；miRNA和靶序列的互补程度决定了靶基因mRNA要不在翻译水平被部分抑制，要不完全断裂（step 7）。植物体中，断裂似乎是主要的工作方式，而哺乳动物中则以翻译水平的抑制为主要方式。

（生物通 小茜）

Febit公司的miRNA表达谱芯片 优惠促销详情请点击

生物通推荐原文检索

Copyright  2010 Elsevier Inc.. All rights reserved.

Cell, Volume 140, Issue 5, 652-665, 5 March 2010

doi:10.1016/j.cell.2010.01.007

 

miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts

Anna M. Eiring1, Jason G. Harb1, Paolo Neviani1, Christopher Garton1, Joshua J. Oaks1, Riccardo Spizzo6, Shujun Liu2, Sebastian Schwind2, 3, Ramasamy Santhanam1, Christopher J. Hickey2, 3, Heiko Becker2, 3, Jason C. Chandler2, Raul Andino5, Jorge Cortes6, Peter Hokland7, Claudia S. Huettner8, Ravi Bhatia9, Denis C. Roy10, Stephen A. Liebhaber11, Michael A. Caligiuri1, 2, 3, Guido Marcucci1, 2, 3, Ramiro Garzon1, 2, 3, Carlo M. Croce1, 3, George A. Calin6 and Danilo Perrotti1, 3, 4, , 

 

1 Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA

2 Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA

3 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

4 Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA

5 Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA

6 Department of Leukemia and Department of Experimental Therapeutics, Center for RNA Interference and Non-Coding RNAs, M.D. Anderson Cancer Center, Houston, TX 77030, USA

7 Department of Hematology, Aarhus University, 8000 Aarhus C, Denmark

8 Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

9 Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA

10 Department of Hematology-Oncology, Maisonneuve-Rosemont Hospital and University of Montreal, Montreal, Quebec H3T 1J4, Canada

11 Department of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

【Summary】

MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.