Mmu-miR-702 functions as an anti-apoptotic mirtron by mediating ATF6 inhibition in mice

Gene. 2013 Dec 1;531(2):235-42. doi: 10.1016/j.gene.2013.09.005. Epub 2013 Sep 10.

Abstract

MicroRNAs (miRNAs) are a group of endogenous, small, noncoding RNAs that function as key post-transcriptional regulators. miRNAs are involved in many biological processes including apoptosis. In this study, mouse miR-702 (mmu-miR-702), a mirtron derived from the 13th intron of the Plod3 gene, was identified as a regulator of anti-apoptosis. mmu-miR-702 was down-regulated after treatment with the apoptosis-inducer isoproterenol both in vivo and in vitro. According to over-expression experiments, mmu-miR-702 inhibited apoptosis as well as the expression levels of a subset of apoptosis-related genes including activating transcription factor 6 (ATF6). An interaction between mmu-miR-702 and the ATF6 3'-UTR binding site was confirmed using luciferase reporter and western blot assays. This is the first report of ATF6 interaction with miRNA. Although the possible existence of miR-702 in the human genome is low, our results indicate that mirtrons also participate in the process of apoptosis and may provide a novel study strategy for apoptosis.

Keywords: 78kDa glucose-regulated protein; ATF6; Apoptosis; B-cell CLL/lymphoma 2; BAX; BCL2; BCL2-associated X protein; C/EBP homologous protein; CHOP; ER; ERSE; GRP78; ISO; Isoproterenol; MicroRNA; Short hairpin introns; UPR; UTR; X-box binding protein 1; XBP1; activating transcription factor 6; endoplasmic reticulum; endoplasmic reticulum stress response element; isoproterenol; miR-702; mmu-miR-702; mouse microRNA-702; unfolded protein response; untranslated regions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / antagonists & inhibitors
  • Activating Transcription Factor 6 / genetics*
  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Endoplasmic Reticulum Chaperone BiP
  • HEK293 Cells
  • Humans
  • Isoproterenol / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • NIH 3T3 Cells

Substances

  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Hspa5 protein, mouse
  • MicroRNAs
  • Mirn702 microRNA, mouse
  • Isoproterenol