Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis

Abstract

The mechanisms by which glucocorticoid receptor (GR) mediates glucocorticoid (GC)-induced apoptosis are unknown. We studied the role of mitochondrial GR in this process. Dexamethasone induces GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T cell lines. In contrast, nuclear GR translocation occurs in all cell types. Thymic epithelial cells, which cause apoptosis of the PD1.6 T cell line in a GR-dependent manner, induce GR translocation to the mitochondria, but not to the nucleus, suggesting a role for mitochondrial GR in eliciting apoptosis. This hypothesis is corroborated by the finding that a GR variant exclusively expressed in the mitochondria elicits apoptosis of several cancer cell lines. A putative mitochondrial localization signal was defined to amino acids 558–580 of human GR, which lies within the NH2-terminal part of the ligand-binding domain. Altogether, our data show that mitochondrial and nuclear translocations of GR are differentially regulated, and that mitochondrial GR translocation correlates with susceptibility to GC-induced apoptosis.

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

“…Two-way ANOVA and Newman-Keulls analysis; *p50.01 vs. control groups. DOI: 10.3109/19396368.2015.1030473 genomic mechanism, the transcription of certain transcription factors, such as c-jun/c-fos and NF-kB (nuclear factor kB) whose target genes are related to cell survival [Greenstein et al 2002;Sionov et al 2006]. Moreover, corticosterone could potentially lead germ cells to apoptosis through the intrinsic apoptotic signaling pathway, as observed during dexamethasone treatment [Yazawa et al 2000], where Bax expression increases at specific androgen-dependent stages (Vll-Vlll) of the seminiferous epithelium cycle [Mahmoud et al 2009].…”

Steroid and thyroid hormone receptors in mitochondria

“…The purification of receptor proteins and the availability of respective antibodies permitted the application of immune techniques, that is Western blotting, immunofluorescence, confocal and immunogold electron microscopy, for the identification of glucocorticoid (GR), estrogen (ER), androgen (AR), and thyroid hormone (TR) receptors in mitochondria (Fig. 2, Table 1) (37,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(66)(67)(68)(69).…”

The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

“…Additionally, it can interact with other transcription factors to affect gene expression indirectly (Kassel and Herrlich, 2007). The localization of glucococorticoid receptor in mitochondria and its implication in the regulation of mitochondrial functions has also been documented (Psarra et al, 2005;Sionov et al, 2006;Sekeris, 2009a, 2011;Psarra et al, 2009b, Du et al, 2009). In addition, binding of GCs to membrane GR can also trigger GCs' non-genomic actions (Borski, 2000).…”