Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway

Park, Jongsun; Leong, Meredith L.; Buse, Patricia; Maiyar, Anita C.; Firestone, Gary L.; Hemmings, Brian A.

doi:10.1093/emboj/18.11.3024

Cited by 507 publications

(647 citation statements)

References 35 publications

(60 reference statements)

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“…SGK1 expression was also highly dependent on IL-6 in INA-6 cells, indicating that SGK1 is a prominent transcriptional target of cytokineinduced signaling in myeloma cells (Supplementary Tables 1b and c; for an overview of SGK1 expression in IH-1, OH-2 and INA-6 cells under different culture conditions see Supplementary Table 1d). As SGK1 exhibits mitogenic and antiapoptotic properties in other cellular systems (Brunet et al, 2001;Leong et al, 2003) and is a component of the PI3K pathway (Kobayashi and Cohen, 1999;Park et al, 1999), which mediates important survival signals for myeloma cells, we decided to analyze the role of SGK1 in MM in more detail.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, SGK1 protein is regulated at the posttranslational level by phosphorylation and subcellular localization. Similarly to AKT, SGK1 is activated through phosphorylation by phosphoinositide-dependent protein kinase-1 (PDK-1), a signaling intermediate downstream of PI3K (Kobayashi and Cohen, 1999;Park et al, 1999). Several myeloma growth factors, like IGF-1 and HGF, are known to activate the PI3K/AKT pathway, and AKT kinase has been shown to provide important growth and survival signals for MM cells (Tu et al, 2000;Hideshima et al, 2001;Hsu et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

et al. 2011

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Multiple myeloma (MM) is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We determined the changes in gene expression induced by interleukin (IL)-6, tumor necrosis factor-a, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokineinduced signaling in myeloma cells was the gene encoding the serine/threonine kinase serum/glucocorticoid-regulated kinase 1 (SGK1), which is a down-stream effector of PI3-kinase. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, small hairpin RNA (shRNA)-mediated knock-down of STAT3 reduced basal and induced SGK1 levels. Furthermore, downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines and reduced cell numbers. On the molecular level, this was reflected by the induction of cell cycle inhibitory genes, for example, CDKNA1/p21, whereas positively acting factors such as CDK6 and RBL2/p130 were downregulated. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

et al. 2011

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“…In fact, Mikosz and coworkers concluded that sgk is a survival kinase, as the expression of sgk corre- lates directly with protection against apoptosis in certain cell lines (Mikosz et al 2001). Sgk itself is directly activated by phosphoinositide-3 kinase, and inactivated by PP2A (Park, et al 1999). Although the downstream targets of sgk are unknown, it has been suggested to phosphorylate and inactivate certain transcription factors in the nucleus, which in turn leads to the promotion of cell survival (Brunet et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…The authors hypothesized that the postsynaptically localized I ␤-␣ and NF ␤ act as messenger molecules that travel from the synapse to the nucleus. Serum glucocorticoid kinase (sgk) is another signaling molecule that is transcriptionally regulated by a variety of stimuli including glucocorticoids, p53, and cell injury (Park et al 1999). LSD induced a twofold expression of the sgk gene in all three regions examined around two fold.…”

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confidence: 99%

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

Nichols

Sanders‐Bush

2002

Neuropsychopharmacology

135

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Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including INTRODUCTIONLysergic acid diethylamide (LSD) is an hallucinogenic drug that transiently but powerfully alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia (Breier 1995). Despite extensive research over the past four decades, the mechanism of action of hallucinogenic drugs still largely remains a mystery. The behavioral effects of LSD are believed to arise in part from agonist activity at the 5-HT 2A , 5-HT 2C , and 5-HT 1A receptor subtypes (Burris et al. 1991; KrebsThomson et al. 1998;Titeler et al. 1988), but if, and how, these interactions affect cognitive functions remains unknown. In addition to actions at serotonin receptors, LSD has high affinity for dopamine receptors and has been shown to act as an agonist at these receptors (Giacomelli et al. 1998;Watts et al. 1995). Because LSD is a unique ligand that can simultaneously bind to serotonin and dopamine receptor subtypes implicated in both normal and abnormal human behaviors, it is an excellent tool for probing the biochemical basis for behavior.Simply increasing brain levels of serotonin, however, does not produce hallucinogenic effects. Recent work has demonstrated that while LSD binds to the same re- NO . 5 LSD-influenced Gene Expression 635 ceptor sites as the endogenous ligand serotonin, it has the capacity to activate different intracellular signaling cascades (Backstrom et al. 1999). Because intracellular signaling cascades influence gene expression, LSDinduced signaling events within cells may inappropriately alter gene expression, which in turn may lead to changes in the physiological status of the neurons, ultimately altering the processes of cognition. Certain behavioral effects of LSD resemble paranoid schizophrenia in humans. This particular subset of mood alterations occurs within the "second phase . . . of the LSD experience" as defined by Freedman, and may be specific for LSD (Freedman 1984). These delayed "second phase" effects could result from transient changes in gene expression. Thus, identifying and characterizing these genes could prove to be important in understanding mechanisms underlying how hallucinogens such as LSD alter behavior. In addition, understanding these mechanisms may lead to the identification of novel therapeutic targets for treatment of mental disorders.We took a broad approach to investigating and identifying genes that are altered by an acute dose of LSD in the mammalian brain. First, we investigated the expression of the mRNAs of the 5-HT receptor subtypes thought to mediate hallucinogenic effects in animal models (5-HT 1A,2A,2C ), as well as, specific gene expression of immediate early genes predicted to be affected by LSD. Next, we performed a DNA microarray screen to identify gene expression influenced by LSD at a more global level. For each gene identified,...

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“…Sgk1 belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids, as well as by an expanding set of hormones, growth factors and cellular stress pathways. 89 Sgk1 is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression and apoptosis. 90 Sgk1 is activated through the phosphatidylinositol 3 kinase (PI3-kinase) pathway by growth factors such as insulin, insulin-like growth factor-1 (IGF1), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) or tumor growth factor beta (TGF-beta), which activate extracellular signal-regulated kinases (ERKs).…”

Section: Number Of Transcripts Affected By Single and Multiple Treatmmentioning

confidence: 99%

Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

et al. 2006

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The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast-and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are:1. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 2. The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system. 3. ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner. 4. Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoidregulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs). 5. Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX.The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.

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Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway

Cited by 507 publications

References 35 publications

Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

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