Article

RNA-Binding Protein HuD Controls Insulin Translation

Laboratory of Molecular Biology and Immunology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Molecular cell (Impact Factor: 14.46). 02/2012; 45(6):826-35. DOI: 10.1016/j.molcel.2012.01.016
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Wook Kim, Jul 07, 2015
0 Followers
 · 
298 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Post-transcriptional gene regulation by microRNAs (miRNAs) and RNA-binding proteins (RBPs) is central to many biological functions. Aberrant gene expression patterns underlie many metabolic diseases that represent major public health concerns and formidable therapeutic challenges. Several studies have established a number of post-transcriptional regulators implicated in metabolic diseases such as diabetes and obesity. In addition, emerging knowledge of metabolically active and insulin-sensitive organs, such as the pancreas, liver, muscle and adipose compartment, is rapidly expanding the panel of potential therapeutic targets for the treatment of metabolic diseases. Here, we review our current understanding of miRNAs and RBPs that affect glucose and lipid homeostasis, and their roles in normal physiology and metabolic disorders, especially type 2 diabetes and obesity.
    RNA biology 06/2012; 9(6):772-80. DOI:10.4161/rna.20091 · 5.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The study utilized an in-silico approach for the discovery of putative G-Quadruplexes in the Human transcripts and its subsequent analysis. Suitable programming codes were devised using the programming language of Perl for the analysis of putative G-Quadruplexes discovered.
    Amity Institute of Biotechnology, Amity University, 08/2012, Degree: M.Tech (Biotechnology), Supervisor: Vinod Scaria
  • [Show abstract] [Hide abstract]
    ABSTRACT: The RBP (RNA-binding protein) and Hu/ELAV family member HuD regulates mRNA metabolism of genes directly or indirectly involved in neuronal differentiation, learning and memory, and several neurological diseases. Given the important functions of HuD in a variety of processes, we set out to determine the mechanisms that promote HuD mRNA expression in neurons using a mouse model. Through several complementary approaches, we determined that the abundance of HuD mRNA is predominantly under transcriptional control in developing neurons. Bioinformatic and 5'RACE (rapid amplification of cDNA ends) analyses of the 5' genomic flanking region identified eight conserved HuD leader exons (E1s), two of which are novel. Expression of all E1 variants was determined in mouse embryonic (E14.5) and adult brains. Sequential deletion of the 5' regulatory region upstream of the predominantly expressed E1c variant revealed a well conserved 400 bp DNA region that contains five E-boxes and is capable of directing HuD expression specifically in neurons. Using EMSA (electrophoretic mobility shift assay), ChIP (chromatin immunoprecipitation), and 5' regulatory region deletion and mutation analysis, we found that two of these E-boxes are targets of Neurogenin 2 (Ngn2) and that this mechanism is important for HuD mRNA induction. Together, our findings reveal that transcriptional regulation of HuD involves the use of alternate leader exons and Ngn2 mediates neuron-specific mRNA expression. To our knowledge, this is the first study to identify molecular events that positively regulate HuD mRNA expression.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(33):11164-75. DOI:10.1523/JNEUROSCI.2247-12.2012 · 6.75 Impact Factor