Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4

Inhibins and activins are gonadal peptide hormones of the transforming growth factor-beta super family with important functions in the reproductive system. By contrast, the recently identified inhibin beta E subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin beta E in hepatoma cells and anti-proliferative effects of ectopic inhibin beta E overexpression indicated growth-regulatory effects of inhibin beta E. We observed a selective re-expression of the inhibin beta E 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 beta E re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin beta E expression in HeLa cells and indicates inhibin beta E as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin beta E subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress. (C) 2012 Elsevier Inc. All rights reserved.