ER stress response during the differentiation of H9 cells induced by retinoic acid

Biochem Biophys Res Commun. 2012 Jan 13;417(2):738-43. doi: 10.1016/j.bbrc.2011.12.026. Epub 2011 Dec 16.


Endoplasmic reticulum (ER) stress occurs during early embryonic development. The aim of this study is to determine whether ER stress occurs during human embryonic stem cell differentiation induced by retinoic acid (RA). H9 human embryonic stem cells were subjected to RA treatment for up to 29days to induce differentiation. HEK293 cells were treated with RA as a control. The results demonstrate that several ER stress-responsive genes are differentially regulated in H9 and HEK293 cells in response to 5days of RA treatment. GRP78/Bip was upregulated in H9 cells but downregulated in HEK293 cells. eIF2α was downregulated in H9 cells but not in HEK293 cells. Phosphorylation of eIF2α was downregulated in H9 cells but upregulated in HEK293 cells. XBP-1 was downregulated immediately after RA treatment in H9 cells, but its downregulation was much slower in HEK293 cells. Additionally, two ER-resident E3 ubiquitin ligases, gp78 and Hrd1, were both upregulated in H9 cells following 5 days of exposure to RA. Moreover, the protein Bcl2 was undetectable in H9 cells and H9-derived cells but was expressed in HEK293 cells, and it expression in the two types of cells was unaltered by RA treatment. In H9 cells treated with RA for 29 days, GRP78/Bip, XBP-1 and Bcl2 were all upregulated. These results suggest that ER stress is involved in H9 cell differentiation induced by RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / physiology*
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Receptors, Autocrine Motility Factor / biosynthesis
  • Tretinoin / pharmacology
  • Tretinoin / physiology*
  • Ubiquitin-Protein Ligases / biosynthesis


  • Eukaryotic Initiation Factor-2
  • Tretinoin
  • AMFR protein, human
  • Receptors, Autocrine Motility Factor
  • SYVN1 protein, human
  • Ubiquitin-Protein Ligases