Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.
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.
Sionov
Ronit Vogt
RV
The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cohen
Orly
O
Kfir
Shlomit
S
Zilberman
Yael
Y
Yefenof
Eitan
E
D017209:Apoptosis; D001692:Biological Transport; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone; D004847:Epithelial Cells / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013950:Thymus Gland
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone