Expression of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, Is a Cell Survival Response to Multiple Types of Environmental Stress Stimuli in Mammary Epithelial Cells

Abstract

The effects of multiple stress stimuli on the cellular utilization of the serum-and glucocorticoid-inducible protein kinase (Sgk) were examined in NMuMg mammary epithelial cells exposed to hyperosmotic stress induced by the organic osmolyte sorbitol, heat shock, ultraviolet irradiation, oxidative stress induced by hydrogen peroxide, or to dexamethasone, a synthetic glucocorticoid that represents a general class of physiological stress hormones. Each of the stress stimuli induced Sgk protein expression with differences in the kinetics and duration of induction and in subcellular localization. The environmental stresses, but not dexamethasone, stimulated Sgk expression through a p38/ MAPK-dependent pathway. In each case, a hyperphosphorylated active Sgk protein was produced under conditions in which Akt, the close homolog of Sgk, remained in its non-phosphorylated state. Ectopic expression of wild type Sgk or of the T256D/S422D mutant Sgk that mimics phosphorylation conferred protection against stress-induced cell death in NMuMg cells. In contrast, expression of the T256A/S422A Sgk phosphorylation site mutant has no effect on cell survival. Sgk is known to phosphorylate and negatively regulate proapoptotic forkhead transcription factor FKHRL1. The environmental stress stimuli that induce Sgk, but not dexamethasone, strongly inhibited the nuclear transcriptional activity and increased the cytoplasmic retention of FKHRL1. Also, the conditional IPTG inducible expression of wild type Sgk, but not of the kinase dead T256A mutant Sgk, protected Con8 mammary epithelial tumor cells from serum starvation-induced apoptosis. Taken together, our study establishes that induction of enzymatically active Sgk functions as a key cell survival component in response to different environmental stress stimuli.

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

“…A previous report demonstrated that SGK-1, but not Akt, is induced by various environmental stress stimuli and then subsequently protects cell from apoptosis induced by environmental stress. 27 Similarly, in this study, we determined that SGK-1 but not other sgk isoforms or Akt was upregulated after androgen stimulation. Our data also demonstrated that SGK-1 is critical for androgen-mediated survival in prostate cancer cells because eliminating SGK-1 expression abrogated androgen-induced death protection.…”

“…These data suggest that SGK-1 elimination leads to apoptosis, which is supported by previous reports. [26][27][28][29] Next, we confirmed that SGK-1 siRNA could induce apoptosis in another prostate cancer cell line. LNCaP cells were tested using a clonogenic assay.…”

“…Similar to Akt, SGK-1 has been shown to be a cellular survival factor. [26][27][28][29] Therefore, we examined the role of SGK-1 in AR-dependent survival of prostate cancer cells. First, we tested if eliminating SGK-1 expression induces apoptosis.…”

“…26,27,29,36 A recent study discovered a novel mechanism that SGK-1 promotes NF-kB survival pathway by activating IKKb. 28 In this study, we found that in AR Figure 7 Proposed mechanism for SGK-1 expression in AR-dependent survival.…”

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…Members of this group include Tsc22d3 (GILZ, Stojadinovic et al, 2007;Ayroldi and Riccardi, 2009) Other genes may display an astrocyte-specific response to GCs. GR-dependent signaling relies on the cellular context (Leong et al, 2003;Yu et al, 2011), which may be associated with the recruitment of cell-type specific GR coactivators (Grenier et al, 2006). The specific function of the GR-dependent genes in astrocytes identified in this work is as yet unknown.…”