Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Neurodevelopmental Hypothesis of the etiology of schizophrenia suggests that interaction between genetic and environmental events occurring during critical early periods in neuronal growth may negatively influence the way by which nerve cells are laid down, differentiated and selectively culled by apoptosis. Recent advances toward understanding the regulation of brain development offer insights into possible mechanisms of developmental brain changes. One such factor is the Wnt family of genes, which plays a central role in normal brain development. Activation of the Wnt cascade leads to inactivation of glycogen synthase kinase-3 beta (GSK-3 beta), accumulation and activation of beta-catenin and expression of genes involved in neuronal development. It has been proposed that alteration in the transduction cascade of the Wnt signaling pathway represents an aberrant neurodevelopment in schizophrenia. The role of GSK-3 in developmental brain changes in schizophrenia may not be restricted to the Wnt signaling cascade. GSK-3 alpha, reported to be 80% lower in lymphocytes of schizophrenic patients is a regulatory enzyme of some neuronal proteins implicated to be aberrant in schizophrenia. Programmed cell death is an essential component of normal brain development. Spatial or temporal errors in the stimuli that initiate this pathway or processes within it can result in pathological neuronal development. Increased density of neuronal population in the cortical subplate, found in postmortem brains of schizophrenic patients may imply reduced programmed cell death. The possible role of GSK-3 beta, a pro-apoptotic factor participating in signal transduction involved in cell survival, is discussed in relation to schizophrenia.
 ...
PMID:[Schizophrenia, neurodevelopment and glycogen synthase kinase-3]. 1451 71

We have developed a general method of making conditional alleles that allows the rapid and reversible regulation of specific proteins. A mouse line was produced in which proteins encoded by the endogenous glycogen synthase kinase-3 beta (GSK-3beta) gene are fused to an 89 amino acid tag, FRB*. FRB* causes the destabilization of GSK-3beta, producing a severe loss-of-function allele. In the presence of C20-MaRap, a highly specific, nontoxic, cell-permeable small molecule, GSK-3betaFRB* binds to the ubiquitously expressed FKBP12 protein. This interaction stabilizes GSK-3betaFRB* and restores both protein levels and activity. C20-MaRap-mediated stabilization is rapidly reversed by the addition of an FKBP12 binding competitor molecule. This technology may be applied to a wide range of FRB*-tagged mouse genes while retaining their native transcriptional control. Inducible stabilization could be valuable for many developmental and physiological studies and for drug target validation.
 ...
PMID:Conditional protein alleles using knockin mice and a chemical inducer of dimerization. 1469 Jun 13

The tumor suppressor p53, a sensor of multiple forms of cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis. We demonstrate that endoplasmic reticulum (ER) stress inhibits p53-mediated apoptosis. The mechanism of inhibition involves the increased cytoplasmic localization of p53 due to phosphorylation at serine 315 and serine 376, which is mediated by glycogen synthase kinase-3 beta (GSK-3beta). ER stress induces GSK-3beta binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3beta and does not occur in cells expressing p53 with mutation(s) of serine 315 and/or serine 376 to alanine(s). As a result of the increased cytoplasmic localization, ER stress prevents p53 stabilization and p53-mediated apoptosis upon DNA damage. It is concluded that inactivation of p53 is a protective mechanism utilized by cells to adapt to ER stress.
 ...
PMID:Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. 1487 24

B cell chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature, functionally incompetent B cells. Wnts are a large family of secreted glycoproteins involved in cell proliferation, differentiation, and oncogenesis. The classical Wnt signaling cascade inhibits the activity of the enzyme glycogen synthase kinase-3beta, augmenting beta-catenin translocation to the nucleus, and the transcription of target genes. Little is known about the potential roles of Wnt signaling in CLL. In this study, we quantified the gene expression profiles of the Wnt family, and their cognate frizzled (Fzd) receptors in primary CLL cells, and determined the role of Wnt signaling in promoting CLL cell survival. Wnt3, Wnt5b, Wnt6, Wnt10a, Wnt14, and Wnt16, as well as the Wnt receptor Fzd3, were highly expressed in CLL, compared with normal B cells. Three lines of evidence suggested that the Wnt signaling pathway was active in CLL. First, the Wnt/beta-catenin-regulated transcription factor lymphoid-enhancing factor-1, and its downstream target cyclin D1, were overexpressed in CLL. Second, a pharmacological inhibitor of glycogen synthase kinase-3 beta, SB-216763, activated beta-catenin-mediated transcription, and enhanced the survival of CLL lymphocytes. Third, Wnt/beta-catenin signaling was diminished by an analog of a nonsteroidal antiinflammatory drug (R-etodolac), at concentrations that increased apoptosis of CLL cells. Taken together, these results indicate that Wnt signaling genes are overexpressed and are active in CLL. Uncontrolled Wnt signaling may contribute to the defect in apoptosis that characterizes this malignancy.
 ...
PMID:Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. 1497 84

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these mutants to co-distribute with the androgen receptor in the cell nucleus, also that both glycogen synthase kinase-3beta and androgen receptor proteins can be found in cell nuclei of prostate cancer tissue samples. Because glycogen synthase kinase-3 beta activity is suppressed after the enzyme is phosphorylated by protein kinase B/Akt and Akt activity frequently increases during the progression of prostate cancer, nullification of the glycogen synthase kinase-3 beta-mediated suppression of androgen receptor activity by Akt likely contributes to prostate cancer progression.
 ...
PMID:Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity. 1498 54

Dehydroepiandrosterone (DHEA) is synthesized in the brain, but whether DHEA is involved in modulating neuronal cell survival is not yet fully understood. Herein we show that when deprived of trophic support, GT1-7 hypothalamic neurons undergo apoptosis following exposure to DHEA, as demonstrated both by morphological and biochemical criteria. This proapoptotic effect appeared to be specific to DHEA itself, and not through conversion of DHEA to other steroids such as androgen or estrogen. Importantly, we determined that IGF-I protects GT1-7 neurons from DHEA-induced cell death. DHEA-induced apoptosis was associated with increased activation of caspase 3 and decreased PARP, which were both attenuated with addition of IGF-I. Addition of DHEA prevented phosphorylation of both Akt and glycogen synthase kinase-3 beta (GSK-3beta), downstream effector molecules of the phosphatidylinositol 3-kinase (PI3K) pathway. Further IGF-I was able to sustain Akt activity and thus preventing GSK-3beta activation in the presence of DHEA. On the other hand, the MAP kinases, ERK, p38, and JNK, were not affected by DHEA. These findings suggest that in GT1-7 hypothalamic neurons, DHEA acts detrimentally to induce cell death and IGF-I is able to rescue the neurons by preserving the activity of Akt, and therefore maintaining the proapoptotic kinase GSK-3beta, in a phosphorylated catalytically inactive state.
 ...
PMID:IGF-I signaling prevents dehydroepiandrosterone (DHEA)-induced apoptosis in hypothalamic neurons. 1506 51

We have previously shown that endogenous IGF-I regulates human intestinal smooth muscle cell proliferation by activation of phosphatidylinositol 3 (PI3)-kinase- and Erk1/2-dependent pathways that jointly regulate cell cycle progression and cell division. Whereas insulin-like growth factor-I (IGF-I) stimulates PI3-kinase-dependent activation of Akt, expression of a kinase-inactive Akt did not alter IGF-I-stimulated proliferation. In other cell types, Akt-dependent phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) inhibits its activity and its ability to stimulate apoptosis. The aim of the present study was to determine whether endogenous IGF-I regulates Akt-dependent GSK-3 beta phosphorylation and activity and whether it regulates apoptosis in human intestinal muscle cells. IGF-I elicited time- and concentration-dependent GSK-3 beta phosphorylation (inactivation) that was measured by Western blot analysis using a phospho-specific GSK-3beta antibody. Endogenous IGF-I stimulated GSK-3 beta phosphorylation and inhibited GSK-3 beta activity (measured by in vitro kinase assay) in these cells. IGF-I-dependent GSK-3 beta phosphorylation and the resulting GSK-3 beta inactivation were mediated by activation of a PI3-kinase-dependent, phosphoinositide-dependent kinase-1 (PDK-1)-dependent, and Akt-dependent mechanism. Deprivation of serum induced beta-catenin phosphorylation, increased in caspase 3 activity, and induced apoptosis of muscle cells, which was inhibited by either IGF-I or a GSK-3 beta inhibitor. Endogenous IGF-I inhibited beta-catenin phosphorylation, caspase 3 activation, and apoptosis induced by serum deprivation. IGF-I-dependent inhibition of apoptosis, similar to GSK-3 beta activity, was mediated by a PI3-kinase-, PDK-1-, and Akt-dependent mechanism. We conclude that endogenous IGF-I exerts two distinct but complementary effects on intestinal smooth muscle cell growth: it stimulates proliferation and inhibits apoptosis. The growth of intestinal smooth muscle cells is regulated jointly by the net effect of these two processes.
 ...
PMID:Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 beta activity. 1529 58

Cisplatin is commonly used in the treatment of advanced ovarian carcinoma. A major limitation of the use of cisplatin is the development of resistance in tumors. Glycogen synthase kinase-3 beta (GSK-3beta) is a multi-functional serine/threonine kinase. Its activity is regulated negatively by the phosphorylation of serine 9 (pGSK-3beta-ser-9) and positively by the phosphorylation of tyrosine 216 (pGSK-3beta-tyr-216). We compared the expression/phosphorylation of GSK-3beta between the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant derivative CP70. The expression levels of total GSK-3beta and pGSK-3beta-tyr-216 were similar in these cells; however, CP70 cells had a much higher expression of pGSK-3beta-ser-9 than A2780 cells. Lithium chloride, which is a GSK-3beta inhibitor and stimulates pGSK-3beta-ser-9, significantly increased the IC50 of cisplatin and counteracted cisplatin-induced apoptosis of A2780 and CP70 cells. In contrast, overexpression of a constitutively active S9A GSK-3beta mutant increased the sensitivity of CP70 cells to cisplatin and significantly enhanced cisplatin-mediated apoptosis. It is suggested that the cisplatin-resistance of CP70 cells is mediated by stabilizing p53. We demonstrated that GSK-3beta negatively regulated the expression of p53. Therefore, pGSK-3beta-ser-9 may confer the cisplatin resistance of ovarian carcinomas through the stabilization of p53 expression. Our study establishes a potential role of GSK-3beta in the development of cisplatin resistance in initially sensitive tumors.
 ...
PMID:Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells. 1767 94

Effective combination antiretroviral therapies (ART) have markedly lengthened survival among HIV infected individuals. In this long-surviving cohort, both psychiatric comorbidities and HIV-associated neurocognitive disorders (HAND) remain common. Even mild neurocognitive impairment can significantly disrupt of activities of daily living and reduce quality of life. Persistence of HAND might reflect incomplete containment of HIV within the central nervous system (CNS) due to the limited penetration of most antiretrovirals (ARVs) across the blood-brain barrier. Recent data support that certain medications used to treat psychiatric comorbidities in HIV-infected individuals may also protect the brain from toxic byproducts of HIV replication and neuroinflammation. Two drug classes in particular, glycogen synthase kinase-3 beta (GSK-3b) inhibitors and serotonin reuptake inhibitors (SRIs), may benefit individuals with HAND. Valproic acid (VPA) and lithium are potentially beneficial GSK-3b inhibitors. While the mechanism of benefit of SRIs in HAND remains unknown, evidence supports some benefit of citalopram and paroxetine. The present brief review focuses on these drugs and assesses their possible adjunct roles in the treatment of HIV-infected individuals.
 ...
PMID:Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders. 1824 65

Increasing evidence implicates the c-Jun NH(2)-terminal kinase (JNK) pathway in the regulation of apoptosis in neurodegenerative diseases. In this study, we examined the neuroprotective effect of SP600125, a selective JNK inhibitor, in cerebellar granule cells (CGNs) deprived of serum and potassium (S/K withdrawal). S/K withdrawal-induced apoptosis occurs via activation of multiple pro-apoptotic pathways, including re-entry into the cell cycle, activation of glycogen synthase kinase-3 beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5/p35) breakdown, formation of cdk5/p25 and JNK activation. Here we demonstrate that SP600125 is able to inhibit all these pro-apoptotic pathways via the inhibition of JNK. Further, we found that JNK inhibition maintains the phosphorylation/activation of Akt after S/K withdrawal. For further confirmation of this result, we studied several targets downstream of Akt including GSK-3beta, p-FOXO1, p-CREB and p35. In addition, the specific PI3K/Akt inhibitor LY294002 greatly diminished the antiapoptotic effects of SP600125 upon S/K withdrawal, confirming that Akt is involved in the neuroprotection achieved by SP600125. These results suggest that the maintenance of the PI3-kinase/Akt pathway by inhibition of JNK contributes to the prevention of apoptosis in rat cerebellar granule neurons mediated by S/K withdrawal. Furthermore, we propose that JNK may regulate the cell cycle re-entry by a novel mechanism that involves Akt, GSK-3beta and Rb phosphorylation.
 ...
PMID:Neuroprotection by c-Jun NH2-terminal kinase inhibitor SP600125 against potassium deprivation-induced apoptosis involves the Akt pathway and inhibition of cell cycle reentry. 1935 94


<< Previous 1 2 3 4 5 6 7 8 Next >>