Erina B. Khotskaya1, Longfei Huo1, Kotaro Nakanishi3, Seung-Oe Lim1, Yi Du1,2, Yan Wang1, Wei-Chao Chang4,five, Chung-Hsuan Chen5, Jennifer L. Hsu1,four,6, Yun Wu7, Yung Carmen Lam1, Brian P. James8, Xiuping Liu8, Chang-Gong Liu8, Dinshaw J. Patel3, and Mien-Chie Hung1,2,4,six 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA2TheUniversity of Texas Graduate College of Biomedical Sciences at Houston, Houston, Texas 77030, USA3StructuralBiology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA4Centerfor Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan5Genomics 6AsiaResearch Center, Academia Sinica, Nankang, Taipei 105, TaiwanUniversity, Taichung 413, Taiwan7Departmentof Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA8Departmentof Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USAAbstractMicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level1. Deregulation of miRNAs has been linked to diverse pathological processes, such as cancer2,3.DSG Crosslinker uses Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses4, such as hypoxia, which is regularly encountered inside the poorly angiogenic core of a solid tumour5. Nevertheless, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the query of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth element receptor (EGFR), which is the item of a well-characterized oncogene in human cancers, suppresses the?013 Macmillan Publishers Restricted. All rights reserved Correspondence and requests for materials should be addressed to M.-C.H. ([email protected]). Supplementary Data is out there inside the on-line version from the paper. Author Contributions J.S. and M.-C.H. made and conceived the study; J.S. and M.-C.H. wrote the manuscript; J.L.H. contributed for the preparation of the manuscript. J.S., W.X., Y.B.K., L.H., S.-O.L., Y.D., Y. Wang, W.-C.C. and C.-H.C. did the experiments; Y. Wu offered human main breast tumour samples; Y.C.L. provided the split-half-YFP-fused constructs; X.L. and C.-G.L. assisted in next-generation RNA deep sequencing; B.Silver(I) 2,2,2-trifluoroacetate Price P.PMID:23329319 J. provided the pipeline evaluation service for RNA sequencing information; and K.N. and D.J.P. analysed the crystal structure of human AGO2. Reprints and permissions info is offered at nature/reprints. The authors declare no competing economic interests. Readers are welcome to comment around the on line version of the paper.Shen et al.Pagematuration of precise tumour-suppressor-like miRNAs in response to hypoxic anxiety by way of phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association among EGFR and AGO2 is enhanced by hypoxia, top to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also determine a long-loop structure in precursor miRNAs as a crucial regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Additionally, AGO2-Y393 phosphorylatio.