한빛사 논문
Abstract
Eun Kyung Lee,1,4,8 Wook Kim,2,8 Kumiko Tominaga,1 Jennifer L. Martindale,1 Xiaoling Yang,1 Sarah S. Subaran,2 Olga D. Carlson,2 Evi M. Mercken,3 Rohit N. Kulkarni,5 Wado Akamatsu,6 Hideyuki Okano,6 Nora I. Perrone-Bizzozero,7 Rafael de Cabo,3 Josephine M. Egan,2 and Myriam Gorospe1,*
1Laboratory of Molecular Biology and Immunology
2Laboratory of Clinical Investigation
3Laboratory of Experimental Gerontology
National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
4Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea
5Department of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
6Department of Physiology, Graduate School of Medicine, Keio University, Shinjuku, Tokyo 160-8582, Japan
7Department of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
8These authors contributed equally to this work
*Correspondence: Myriam Gorospe
Summary
Although expression of the mammalian RNA-binding protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5 untranslated region (UTR) of preproinsulin (Ins2) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.
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