receptor for activated protein kinase c requirement for efficient microrna function and reduced expression in hepatocellular carcinoma受体激活蛋白激酶c要求高效的微rna的功能和降低肝细胞癌中表达.pdfVIP

Receptor for Activated Protein Kinase C: Requirement for Efficient MicroRNA Function and Reduced Expression in Hepatocellular Carcinoma 1 1 1 1 1 Motoyuki Otsuka *, Akemi Takata , Takeshi Yoshikawa , Kentaro Kojima , Takahiro Kishikawa , 1 2 1 1¤ 1 Chikako Shibata , Mutsuhiro Takekawa , Haruhiko Yoshida , Masao Omata , Kazuhiko Koike 1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2 Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan Abstract MicroRNAs (miRNAs) are important regulators of gene expression that control physiological and pathological processes. A global reduction in miRNA abundance and function is a general trait of human cancers, playing a causal role in the transformed phenotype. Here, we sought to newly identify genes involved in the regulation of miRNA function by performing a genetic screen using reporter constructs that measure miRNA function and retrovirus-based random gene disruption. Of the six genes identified, RACK1, which encodes ‘‘receptor for activated protein kinase C’’ (RACK1), was confirmed to be necessary for full miRNA function. RACK1 binds to KH-type splicing regulatory protein (KSRP), a member of the Dicer complex, and is required for the recruitment of mature miRNAs to the RNA-induced silencing complex (RISC). In addition, RACK1 expression was frequently found to be reduced in hepatocellular carcinoma. T