Glucocorticoids induce mitochondrial gene transcription in HepG2 cells Role of the mitochondrial glucocorticoid receptor

被引:120
作者
Psarra, Anna-Maria G. [1 ,2 ]
Sekeris, Constantine E. [3 ]
机构
[1] Univ Thessaly, Dept Biochem & Biotechnol, Larisa 41221, Greece
[2] Acad Athens, Ctr Basic Res, Biomed Res Fdn, Athens 11527, Greece
[3] Natl Hellen Res Fdn, Inst Biol Res & Biotechnol, Mol Endocrinol Lab, Athens 11635, Greece
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2011年 / 1813卷 / 10期
关键词
Glucocorticoid receptor; Mitochondrial transcription; OXPHOS; Mitochondrial transcription factor; Mitochondrial DNA; Mitochondrial ATP production; THYROID-HORMONE RECEPTORS; NUCLEOLAR RNA-SYNTHESIS; PRIMARY SITE; RAT-LIVER; ALPHA-AMANITIN; IN-VIVO; SIMILARITY; SEQUENCES; ELEMENTS; STAT3;
D O I
10.1016/j.bbamcr.2011.05.014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucocorticoids are major regulators of a plethora of cellular functions, acting on target cells through glucocorticoid receptors (GR) and modulation of gene transcription, among other mechanisms. One main site of action of glucocorticoids is the hepatocyte, which responds to the hormonal stimulus with induction of several proteins among them enzymes of oxidative phosphorylation (OXPHOS), both nuclearly and mitochondrially encoded. The induction of OXPHOS is regarded as a result of a nuclear action of the receptor on the respective nuclear genes and on genes encoding mitochondrial transcription factors. The presence of GR in mitochondria and of sequences in the mitochondrial genome similar to glucocorticoid responsive elements, suggested a direct action of GR on mitochondrial transcription. We demonstrate in HepG2 hepatocarcinoma cells specific binding of GR to the regulatory D-loop region of the mitochondrial genome and show that dexamethasone induces the mitochondrial transcription factors A, B1, and B2, the mitochondrial ribosomal RNA, and several mitochondrially encoded OXPHOS genes. Applying a-amanitin, the specific inhibitor of DNA-dependent RNA polymerase II, the dexamethasone-induced transcription of the mitochondrial genes can still proceeds, whereas the DEX effect on transcription of the mitochondrial transcription factors is suppressed. Moreover, HepG2 cells overexpressing mitochondria! targeted GR showed increased RNA synthesis, cytrochrome oxidase subunit I protein expression, and mitochondrial ATP production. We conclude that glucocorticoids can stimulate directly mitochondrial transcription by the mitochondrially localized GR, affecting OXPHOS enzyme biosynthesis. This takes place in addition to their action on mitochondrial genes by way of induction of the nuclearly encoded mitochondrial transcription factors. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1814 / 1821
页数:8
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