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J. Biol. Chem., Vol. 280, Issue 13, 12690-12699, April 1, 2005

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Involvement of Hu and Heterogeneous Nuclear Ribonucleoprotein K in Neuronal Differentiation through p21 mRNA Post-transcriptional Regulation^*

Masato Yano, Hirotaka J. Okano¶, and Hideyuki Okano

From the CREST-JST and the Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan and the Department of Cell Biology and Neuroscience (A1), Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

The Hu family is a group of neuronal RNA-binding proteins required for neuronal differentiation in the developing nervous system. Previously, Hu proteins have been shown to enhance the stabilization and/or translation of target mRNAs, such as p21 (CIP1), by binding to AU-rich elements in untranslated regions (UTRs). In this study, we show that Hu induces p21 expression, cell cycle arrest, and neuronal differentiation in mouse neuroblastoma N1E-115 cells. p21 expression is also up-regulated during Me₂SO-induced differentiation in N1E-115 cells and is controlled by post-transcriptional mechanisms through its 3'-UTR. To investigate the molecular mechanisms of Hu functions, we used a proteomics strategy to isolate Hu-interacting proteins and identified heterogeneous nuclear ribonucleoprotein (hnRNP) K. hnRNP K also specifically binds to CU-rich sequences in p21 mRNA 3'-UTR and represses its translation in both nonneuronal and neuronal cells. Further, using RNA interference experiments, we show that the Hu-p21 pathway contributes to the regulation of neurite outgrowth and proliferation in N1E-115 cells, and this pathway is antagonized by hnRNP K. Our results suggest a model in which the mutually antagonistic action of two RNA-binding proteins, Hu and hnRNP K, control the timing of the switch from proliferation to neuronal differentiation through the post-transcriptional regulation of p21 mRNA.

Received for publication, September 28, 2004 , and in revised form, December 27, 2004.

^* This work was supported by grants from The Ministry of Education, Culture, Sports, Science and Technology (MEXT); CREST-JST; a National Grant-in-aid for the Establishment of a High-Tech Research Center in a Private University; the Keio Medical Association; a grant from the Keio University Hospital Health Center (to H. J. O. and H. O.); and the Japan Society for the Promotion of Science (to M. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: 81-3-5363-3747; Fax: 81-3-3357-5445; E-mail: hjokano{at}sc.itc.keio.ac.jp.

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