title: MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis.
abstract: Pregestational diabetes significantly increases the risk of neural tube defects (NTDs). Maternal diabetes activates an Apoptosis Signal-regulating Kinase 1 (ASK1)-initiated pathway, which triggers neural stem cell apoptosis of the developing neuroepithelium leading to NTD formation. How high glucose of diabetes activates ASK1 is still unclear. In this study, we investigated the mechanism underlying high glucose-induced ASK1 activation. High glucose suppressed miR-17 expression, which led to an increase in its target gene Txnip (Thioredoxin-interacting protein). High glucose-increased Txnip enhanced its binding to the ASK1 inhibitor, thioredoxin (Trx), and thereby sequestered Trx from the Trx-ASK1 complex. High glucose-induced ASK1 activation and consequent apoptosis were abrogated by either the miR-17 mimic or Txnip siRNA knockdown. In contrast, the miR-17 inhibitor or Txnip ectopic overexpression mimicked the stimulative effect of high glucose on ASK1 and apoptosis. Thus, our study demonstrated that miR-17 repression mediates the pro-apoptotic effect of high glucose, and revealed a new mechanism underlying ASK1 activation, in which decreased miR-17 removes Trx inhibition on ASK1 through Txnip.
authors.affiliation: *Department of Obstetrics, Gynecology and Reproductive Sciences;
authors.forename: Daoyin
authors.initials: D
authors.lastname: Dong
authors.affiliation: *Department of Obstetrics, Gynecology and Reproductive Sciences;
authors.forename: Noah
authors.initials: N
authors.lastname: Fu
authors.affiliation: *Department of Obstetrics, Gynecology and Reproductive Sciences; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201 pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016640:Diabetes, Gestational / Q000097:blood / Q000235:genetics; D015536:Down-Regulation; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D005947:Glucose / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D054259:Neural Tube / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C445672:Txnip protein, mouse; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D005947:Glucose
keywords: ASK1 activation; apoptosis; high glucose; maternal diabetes; miR-17; teratogenicity