Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Abstract

Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3␤ (GSK3␤) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3␤ pathways.S erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1-3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4, 5). SGK1 shares its functions and some substrates with another kinase from the AGC family, protein kinase B (PKB/ Akt). Akt, like SGK1, has been shown to mediate cell survival through various signaling cascades and gets activated by a wide range of extracellular stimuli (6). SGK1 lacks the pleckstrin homology (PH) domain that tethers Akt to the plasma membrane, making SGK1 more accessible to cytosolic and nuclear sites and thereby providing it with cellular functions and substrates that do not overlap those of Akt (1, 6). SGK1 plays a protective role in oxidative stress conditions as small interfering RNA (siRNA) knockdown of SGK1 has shown an increase in oxidative stressinduced cell death in HEK293 cells (7). Oxidative stress is a hallmark of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) (8). In a study published in 2005 by Schoenebeck et al., upregulation of SGK1 was seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and in a transgenic model of ALS (SOD1-G93A), and protection from cell death was observed for animals treated with dexamethasone (De...

Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection

“…We hypothesized that Sgk-1 was able to phosphorylate and inactivate a kinase targeting the Ser448 residue of Nedd4-2 (residue known to be phosphorylated by several kinases [43]). Sek-1, known to be inactivated by Sgk-1 [44], is part of the Sgk-1 signaling pathway leading to cell resistance [45], and is already described for regulating p53 expression [46]. Sek-1 protein content was indeed found to be phosphorylated and thus inactivated, and was also dramatically decreased in O3V cells.…”

Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer

“…In particular, SGK1 has been shown to promote antioxidant responses during pregnancy that are essential for fetal development, and exert protective effects in Parkinson’s disease ( 86 ). SGK1 can negatively regulate JNK signaling, an important inducer of superoxide species by modulating complex I activity of the electron transport chain ( 87 , 88 ). In addition, SGK1-mediated inactivation of GSK3-β facilitates MCL1 localization to the mitochondria to significantly reduce mitochondrial ROS production through inhibition of NOX4 expression, adversely affecting the response to chemotherapy ( 88 , 89 ).…”

“…SGK1 can negatively regulate JNK signaling, an important inducer of superoxide species by modulating complex I activity of the electron transport chain ( 87 , 88 ). In addition, SGK1-mediated inactivation of GSK3-β facilitates MCL1 localization to the mitochondria to significantly reduce mitochondrial ROS production through inhibition of NOX4 expression, adversely affecting the response to chemotherapy ( 88 , 89 ). It is important to note, however, that in models of lung cancer, MCL1 may also promote ROS production from the mitochondria by binding to voltage-dependent anion channels and increasing the mitochondrial flux of calcium ( 90 ).…”

Genetic mutations you want

“…Inhibitors of CETP, studied by Barzilai, have been explored as cholesterol drugs, although none has reached the market. And 23andMe's discovery that some SGK1 mutations protect against Parkinson's has been followed up with basic research showing that blocking SGK1, a protein known to mediate the way cells respond to stress, can turn off pathways involved in neurodegeneration (14). The advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing technology offers still more possibilities for developing therapies based on beneficial gene mutations.…”