Serine/threonine-protein phosphatase 2A regulatory subunit B subunit gamma (Protein phosphatase subunit G5PR) (Rhabdomyosarcoma antigen MU-RMS-40.6A/6C) [C14orf10] [G5PR]

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The mir-465 family is upregulated with age and attenuates growth hormone signaling in mouse liver.

We analyzed the small RNA transcriptome from 5-month-old, 24-month-old, and 36-month-old mouse liver and found 56 miRNAs that changed their expression profile with age. Among these is a cluster of 18 miRNAs that are upregulated between 50- and 1,000-fold at 24 and 36 months of age. This cluster is located in a 60-kb region of the X-chromosome that is devoid of other coding sequences and is part of a lamin-associated domain. Potential targets of the miRNAs in the cluster suggest they may regulate several pathways altered in aging, including the PI3K-Akt pathway. Total transcriptome analyses indicate that expression of several potential genes in the PI3K-Akt pathway that may be targeted by the mir-465 family (mmu-mir-465a, mmu-mir-465b, and mmu-mir-465c) is downregulated with age. Transfection of the liver cell line AML12 with mir-465 family members leads to a reduction of three of these potential targets at the mRNA level: a 40% reduction of the growth hormone receptor (GHR), and a 25% reduction in Kitl and PPP2R3C. Further investigation of the GHR 3'UTR revealed that the mir-465 family directly targets the GHR mRNA. Cells transfected with mir-465 showed a reduction of JAK2 and STAT5 phosphorylation upon growth hormone (GH) stimulation, resulting in a reduction in insulin-like growth factor 1 (IGF-1) and IGF-1-binding protein 3 expression. With age, GH signaling falls and there is a reduction in circulating IGF-1. Our data suggest that an increase in expression of the mir-465 family with age may contribute to the reduction in the GH signaling.

MeSH Terms

  • Aging
  • Animals
  • Growth Hormone
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs
  • Signal Transduction
  • Up-Regulation

Keywords

  • aging
  • growth hormone receptor
  • growth hormone signaling
  • liver
  • miRNAs
  • mouse