Τίτλος:
Crosstalk between C/EBP homologous protein (CHOP) and glucocorticoid receptor in lung cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Loss of homeostasis triggers the endoplasmic reticulum (ER) stress response and activates the unfolded protein response (UPR) resulting in the induction of the CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP). Glucocorticoids (GCs), via the glucocorticoid receptor (GR), regulate numerous physiological processes in an effort to maintain homeostasis. Previous studies demonstrated that glucocorticoids suppress ER stress by enhancing correct folding of secreted proteins and degradation of misfolded proteins. Here, we describe a novel crosstalk between ER-stress and the glucocorticoid receptor signaling. We showed that treatment of wild type mice with Tunicamycin (inducer of ER-stress) increased GR protein levels in the lungs. Treatment of A549 cells (human lung cancer cells) with ER stress inducers modulated the Dexamethasone-induced subcellular localization of GR and the phosphorylated forms of GR (pGRSer211 and pGRSer203) with concomitant changes in the expression of primary GR-target genes. We demonstrated a significant protein-protein interaction between GR and CHOP, (GR-CHOP heterocomplex formation) under ER stress conditions. The functional consequences of ER stress- GR signaling crosstalk were assessed and demonstrated that long time exposure (24–48 h) of A549 cells to dexamethasone (10−6 M) reversed the Tunicamycin-induced cell death, a phenomenon associated with parallel increases in GR protein content, increases in cell survival parameters and decreases in cell apoptosis-related parameters. Our study provides evidence that there is a cross talk between ER-stress and GR signaling, this being associated with mutual functional antagonism between CHOP and GR-mediated pathways in lung cells with important implications in lung cell function. © 2016
Συγγραφείς:
Mihailidou, C.
Panagiotou, C.
Kiaris, H.
Kassi, E.
Moutsatsou, P.
Περιοδικό:
Molecular and Cellular Endocrinology
Εκδότης:
Elsevier Ireland Ltd
Λέξεις-κλειδιά:
caspase; dexamethasone; glucocorticoid receptor; growth arrest and DNA damage inducible protein 153; serine; tunicamycin; caspase; dexamethasone; glucocorticoid receptor; growth arrest and DNA damage inducible protein 153; messenger RNA; phosphoserine; protein binding; tunicamycin, adult; animal experiment; apoptosis; Article; cell survival; cell viability; cellular distribution; CIDEC gene; controlled study; cytoplasm; DUSP1 gene; endoplasmic reticulum stress; enzyme activity; female; FKBP5 gene; gene; gene expression; gene targeting; GILZ gene; human; human cell; in vitro study; in vivo study; lung cancer; mouse; nonhuman; priority journal; protein expression; protein localization; protein phosphorylation; protein protein interaction; signal transduction; time; A-549 cell line; animal; C57BL mouse; cell compartmentalization; cell nucleus; cytosol; drug effects; endoplasmic reticulum stress; gene expression regulation; genetics; lung tumor; metabolism; pathology; phosphorylation; protein transport; time factor, A549 Cells; Animals; Apoptosis; Caspases; Cell Compartmentation; Cell Nucleus; Cell Survival; Cytosol; Dexamethasone; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Mice, Inbred C57BL; Phosphorylation; Phosphoserine; Protein Binding; Protein Transport; Receptors, Glucocorticoid; RNA, Messenger; Time Factors; Transcription Factor CHOP; Tunicamycin
DOI:
10.1016/j.mce.2016.08.001
