High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress.

Abstract

High glucose in vivo and in vitro induces neural tube defects (NTDs). CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is essential for neural tube closure. We explored the regulatory mechanism underlying CITED2 expression and its relationship with miRNA and endoplasmic reticulum (ER) stress. miR-200b levels were increased by maternal diabetes or high glucose in vitro, and this increase was abrogated by transgenic overexpression of superoxide dismutase 1 (SOD1) or an SOD1 mimetic. CITED2 was the target of miR-200b and was downregulated by high glucose. Two miR-200b binding sites in the 3'-untranslated region of the CITED2 mRNA were required for inhibiting CITED2 expression. The miR-200b mimic and a CITED2 knockdown mimicked the stimulative effect of high glucose on unfolded protein response (UPR) and ER stress, whereas the miR-200b inhibitor and CITED2 overexpression abolished high glucose-induced UPR signaling, ER stress, and apoptosis. The ER stress inhibitor, 4-phenylbutyrate, blocked CITED2 knockdown-induced apoptosis. Furthermore, the miR-200b inhibitor reversed high glucose-induced CITED2 downregulation, ER stress, and NTDs in cultured embryos. Thus, we showed a novel function of miR-200b and CITED2 in high glucose-induced UPR and ER stress, suggesting that miR-200b and CITED2 are critical for ER homeostasis and NTD formation in the developing embryo.

• Authors: Hui Gu, Jingwen Yu, Daoyin Dong, Qun Zhou, Jian-Ying Wang, Shengyun Fang, Peixin Yang
• Journal: Diabetes (Diabetes) Vol. 65 Issue 1 Pg. 149-63 (Jan 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 26450995 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• 3' Untranslated Regions
• Blood Glucose
• Cited2 protein, mouse
• MicroRNAs
• Mirn200 microRNA, mouse
• Phenylbutyrates
• RNA, Messenger
• Repressor Proteins
• Trans-Activators
• 4-phenylbutyric acid
• Sod1 protein, mouse
• Superoxide Dismutase
• Superoxide Dismutase-1

Topics

• 3' Untranslated Regions
• Animals
• Apoptosis (genetics)
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (embryology, genetics, metabolism)
• Embryo, Mammalian
• Endoplasmic Reticulum Stress (genetics)
• Female
• Gene Knockdown Techniques
• Immunoblotting
• In Situ Nick-End Labeling
• In Vitro Techniques
• Mice
• Mice, Transgenic
• MicroRNAs (genetics)
• Neural Stem Cells
• Neural Tube Defects (embryology, genetics, metabolism)
• Phenylbutyrates (pharmacology)
• Pregnancy
• RNA, Messenger (metabolism)
• Repressor Proteins (genetics, metabolism)
• Superoxide Dismutase (genetics)
• Superoxide Dismutase-1
• Trans-Activators (genetics, metabolism)
• Unfolded Protein Response (genetics)