title: Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4.
abstract: Inhibins and activins are gonadal peptide hormones of the transforming growth factor-β super family with important functions in the reproductive system. By contrast, the recently identified inhibin βE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin βE in hepatoma cells and anti-proliferative effects of ectopic inhibin βE overexpression indicated growth-regulatory effects of inhibin βE. We observed a selective re-expression of the inhibin βE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin βE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin βE expression in HeLa cells and indicates inhibin βE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin βE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress.
authors.affiliation: Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich, Munich, Germany. ansgar.bruening@med.uni-muenchen.de
authors.forename: Ansgar
authors.initials: A
authors.lastname: Brüning
authors.forename: Christina
authors.initials: C
authors.lastname: Matsingou
authors.forename: German Johannes
authors.initials: GJ
authors.lastname: Brem
authors.forename: Martina
authors.initials: M
authors.lastname: Rahmeh
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mylonas
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D018390:Gene Targeting; D006367:HeLa Cells; D006801:Humans; D028322:Inhibin-beta Subunits / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D019888:Nelfinavir / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C504183:INHBE protein, human; D051701:Activating Transcription Factor 4; D028322:Inhibin-beta Subunits; D019888:Nelfinavir