The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells

Abstract

Glucocorticoids (GC) are important in the regulation of selection and apoptosis of CD4+CD8+ double-positive (DP) thymocytes. The pronounced GC-sensitivity of DP thymocytes, observed earlier, might be due to the combination of classical (genomic) and alternative (non-genomic) glucocorticoid receptor (GR) signaling events modifying activation or apoptotic pathways. In particular, the previously demonstrated mitochondrial translocation of activated GR in DP thymocytes offered a fascinating explanation for their pronounced GC-induced apoptosis sensitivity. However, the fine molecular details how the mitochondrial translocation of GR might regulate apoptosis remained unclear. Therefore, in the present study, we intended to examine which apoptotic pathways could be involved in GC-induced thymocyte apoptosis. Furthermore we investigated the potential relationship between the GR and Bcl-2 proteins. Using an in vitro test system, thymocytes from 4-week-old BALB/c mice, were treated with the GC-analogue dexamethasone (DX). Bax accumulated in mitochondria upon DX treatment. Mitochondrial GR showed association with members of the Bcl-2 family: Bak, Bim, Bcl-xL. Elevated Cytochrome C, and active caspase-3, -8, and -9 levels were detected in thymocytes after DX treatment. These results support the hypothesis that in early phases of GC-induced thymocyte apoptosis, the mitochondrial pathway plays a crucial role, confirmed by the release of Cytochrome C and the activation of caspase-9. The activation of caspase-8 was presumably due to cross-talk between apoptotic signaling pathways. We propose that the GC-induced mitochondrial accumulation of Bax and the interaction between the GR and Bim, Bcl-xL and Bak could play a role in the regulation of thymocyte apoptosis.

Induction of apoptosis in nasal polyp-derived fibroblasts by bleomycin A5 in�vitro

“…Pro-apoptotic proteins can induce apoptosis through breakage of the mitochondrial membrane potential (22). To the contrary, by binding to specific site of Bax, the anti-apoptotic proteins retained normal permeability and prevented the release of mitochondrial pro-apoptotic factors into the cytoplasm (23). Thus, the balance of pro-apoptotic and anti-apoptotic proteins is often used to regulate cell apoptosis (17).…”

Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase‐3β/β‐catenin pathway

“…Endogenous apoptosis is marked by the release of cytochrome C followed by pro‐caspase‐9 activation, both of which participate in constituting the apoptosome and activating several executioners. Finally, two pathways result in the cleavage of caspase‐3 and PARP1, recognized to be the executants of cell apoptosis . The Bcl‐2 family also plays a vital role in either prompting (Bax and Bak) or suppressing (Bcl‐2 and Bcl‐xl) apoptosis .…”

“…Finally, two pathways result in the cleavage of caspase-3 and PARP1, recognized to be the executants of cell apoptosis. (27,28) The Bcl-2 family also plays a vital role in either prompting (Bax and Bak) or suppressing (Bcl-2 and Bcl-xl) apoptosis. (29) Bcl-2 has been verified to be able to terminate apoptosis by attenuating the release of cytochrome C to inactivate caspase.…”

Mitochondrial Hormone Receptors - an Emerging Field of Signaling in the Cell’s Powerhouse

“…In another pioneering study, which was, however, poorly considered for several years, a GR response element (GRE) was shown to be present in a D-loop of the mitochondrial chromosome [2]. Meanwhile, several investigations have demonstrated GR translocation to mitochondria [1][2][3][4][5], a process that depends on glucocorticoid availability [1][2][3][4][5] and on a mechanism reminiscent of the transfer into the nucleus, also involving heat shock proteins and an immunophilin [4].…”

“…In addition, the mitochondrial GR seems to be involved in apoptosis induction in thymocytes, which may not be surprising with regard to the presence of the proapoptotic machinery in this organelle [5]. Mitochondrial localization has been multiply shown for the estrogen receptor-β (ERβ) [6,7], the ER variant anyway known for its nongenomic signaling.…”