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)

Members of the Wnt family of signaling molecules are important in cell specification and epithelial-mesenchymal interactions, and targeted gene deletion of Wnt-7a in mice results in complete absence of uterine glands and infertility. To assess potential roles of the Wnt family in human endometrium, an endocrine-responsive tissue, we investigated in the proliferative and secretory phases of the menstrual cycle, endometrial expression of several Wnt ligands (Wnt-2, Wnt-3, Wnt-4, Wnt-5a, Wnt-7a, and Wnt-8b), receptors [Frizzled (Fz)-6 and low-density lipoprotein receptor-related protein (LRP)-6], inhibitors [FrpHE and Dickkopf (Dkk)-1], and downstream effectors (Dishevelled-1, glycogen synthase kinase-3beta, and beta-catenin) by RT-PCR, real-time PCR and in situ hybridization. No significant menstrual cycle dependence of the Wnt ligands (except Wnt-3), receptors, or downstream effectors, was observed. Wnt-3 increased 4.7-fold in proliferative compared with secretory endometrium (P < 0.05). However, both inhibitors showed dramatic changes during the cycle, with 22.2-fold down-regulation (P < 0.05) of FrpHE and 234.3-fold up-regulation (P < 0.001) of Dkk-1 in the secretory, compared with the proliferative phase. In situ hybridization revealed cell-specific expression of different Wnt family genes in human endometrium. Wnt-7a was exclusively expressed in the luminal epithelium, and Fz-6 and beta-catenin were expressed in both epithelium and stroma, without any apparent change during the cycle. Both FrpHE and Dkk-1 expression were restricted to the stroma, during the proliferative and secretory phase, respectively. These unique expression patterns of Wnt family genes in different cell types of endometrium and the differential regulation of the inhibitors during the proliferative and secretory phase of the menstrual cycle strongly suggest functions for a Wnt signaling dialog between epithelial and stromal components in human endometrium. Also, they underscore the likely importance of this family during endometrial development, differentiation and implantation.
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PMID:Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium. 1291 80

We used primary cultures of cortical neurons to examine the relationship between beta-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to beta-amyloid peptide (betaAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3beta. DKK1 was induced at late times after betaAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in betaAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by beta-amyloid and is critically involved in the process of tau phosphorylation.
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PMID:Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. 1522 49

Through their broad differentiation potential, mesenchymal stem cells (MSCs) are candidates for a range of therapeutic applications, but the precise signaling pathways that determine their differentiated fate are not fully understood. Evidence is emerging that developmental signaling cues may be important in regulating stem cell self-renewal and differentiation programs. Here we have identified a consistent expression profile of Wnt signaling molecules in MSCs and provide evidence that an endogenous canonical Wnt pathway functions in these cells. Wnts bind to Frizzled (Fz) receptors and subsequent canonical signaling inhibits glycogen synthase kinase-3beta (GSK-3beta), causing beta-catenin translocation into the nucleus to induce target gene expression. In human MSCs isolated from bone marrow of different donors, we appear to have identified a common Wnt/Fz expression profile using reverse transcriptase polymerase chain reaction (RT-PCR). Associated Wnt signaling components, including low-density lipoprotein receptor-related protein-5 (LRP-5), kremen-1, dickkopf-1 (Dkk-1), secreted Frizzled-related peptide (sFRP)-2, sFRP3, sFRP4, Disheveled (Dvl), GSK-3beta, adenomatous polyposis coli (APC), beta-catenin,T-cell factor (TCF)-1, and TCF-4, were also identified. Nuclear beta-catenin was observed in 30%-40% of MSCs, indicative of endogenous Wnt signaling. Exposure to both Wnt3a and Li+ ions, which promotes canonical Wnt signaling by inhibiting GSK-3beta, reduced phosphorylation of beta-catenin in MSCs and increased beta-catenin nuclear translocation approximately threefold over that of the controls. Our findings indicate that autocrine Wnt signaling operates in primitive MSC populations and supports previous evidence that Wnt signaling regulates mesenchymal lineage specification. The identification of a putative common Wnt/Fz molecular signature in MSCs will contribute to our understanding of the molecular mechanisms that regulate self-renewal and lineage-specific differentiation.
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PMID:Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. 1534 48

To explore the mechanism of glucocorticoid-induced osteoporosis, we investigated the effect of glucocorticoid on canonical Wnt signaling that emerged as a novel key pathway for promoting bone formation. Wnt3a increased the T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent transcriptional activity in primary cultured human osteoblasts. Dexamethasone suppressed this transcriptional activity in a dose-dependent manner, while 1,25-dihydroxyvitamin D3 increased this transcriptional activity. LiCl, an inhibitor of glycogen synthase kinase-3beta, also enhanced the Tcf/Lef-dependent transcriptional activity, which was, however, not inhibited by dexamethasone. The addition of anti-dickkopf-1 antibody partially restored the transcriptional activity suppressed by dexamethasone. Dexamethasone decreased the cytosolic amount of beta-catenin accumulated by Wnt3a and also inhibited the nuclear translocation of beta-catenin induced by Wnt3a. These data suggest that glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts, partially through the enhancement of the dickkopf-1 production.
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PMID:Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts. 1572 Dec 90

Members of both Wnt and bone morphogenetic protein (BMP) families of signaling molecules are important in heart development. We previously demonstrated that beta-catenin, a key downstream intermediary of the canonical Wnt signaling pathway, delineates the dorsal boundary of the cardiac compartments in an anteroposterior progression. We hypothesized the progression involves canonical Wnt signaling and reflects development of the primary body axis of the embryo. A similar anteroposterior signaling wave leading to cardiac cell specification involves inductive signaling by BMP-2 synthesized by the underlying endoderm in anterior bilateral regions. Any molecule that disrupts the normal balance of Wnt and BMP concentrations within the heart field may be expected to affect early heart development. The canonical Wnt signaling step mimicked by lithium involves inactivation of glycogen synthase kinase-3beta (GSK-3beta; Klein and Melton [1996] Proc. Natl. Acad. Sci. U. S. A. 93:8455-8459). We show that lithium, Wnt-3A, and an inhibitor of GSK-3beta, SB415286, affect early heart development at the cardiac specification stages. We demonstrate that normal expression patterns of key signaling molecules as Notch-1 and Dkk-1 are altered in the anterior mesoderm within the heart fields by a one-time exposure to lithium, or by noggin inhibition of BMP, at Hamburger and Hamilton (HH) stage 3 during chick embryonic development. The severity of developmental defects is greatest with exposure to lithium or Wnt-3A at HH stage 3 and decreases at HH stage 4. Taken together, our results demonstrate that there are temporal-specific responses and differential sensitivities to lithium/Wnt-3A exposure during early heart development.
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PMID:Early temporal-specific responses and differential sensitivity to lithium and Wnt-3A exposure during heart development. 1680 95

Expression of the Wnt antagonist Dickkopf-1 (DKK1) is induced during neurodegenerative processes associated with Alzheimer's Disease and brain ischemia. However, little is known about DKK1-mediated effects on neurons. We now describe that, in cultured neurons, DKK1 is able to inhibit canonical Wnt signaling, as assessed by TCF reporter assay and analysis of beta-catenin levels, and to elicit cell death associated with loss of BCL-2 expression, induction of BAX, and TAU hyperphosphorylation. Local infusion of DKK1 in rats caused neuronal cell death and astrocytosis in the CA1 region of the hippocampus and death of cholinergic neurons in the nucleus basalis magnocellularis. Both effects were reversed by systemic administration of lithium ions, which rescue the Wnt pathway by inhibiting glycogen synthase kinase-3beta. The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hypothesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders.
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PMID:Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1. 1691 65

Wnt signaling plays an important role not only in development and morphogenesis of embryos but in pathogenesis of various disorders including cancers. Analyses of the mutations in LDL receptor-related protein 5 (LRP5), a Wnt co-receptor, revealed that the Wnt signaling pathway is important for bone formation. Glucocorticoids suppress the canonical Wnt signaling pathway by such mechanisms as the enhancement the expression of dickkopf-1 (Dkk-1) and secreted frizzled-related protein 1 (sFRP1), and activation of the glycogen synthase kinase-3beta (GSK-3beta) activity. The inhibition of the canonical Wnt signal by glucocorticoid may be involved in the pathogenesis of glucocorticoid-induced osteoporosis.
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PMID:[Wnt signaling and glucocorticoid-induced osteoporosis]. 1707 47

Inhibition of the Wnt pathway by the secreted glycoprotein, Dickkopf-1 (Dkk-1) has been related to processes of excitotoxic and ischemic neuronal death. We now report that Dkk-1 is induced in neurons of the rat olfactory cortex and hippocampus degenerating in response to seizures produced by systemic injection of kainate (12 mg/kg, i.p.). There was a tight correlation between Dkk-1 expression and neuronal death in both regions, as shown by the different expression profiles in animals classified as "high" and "low" responders to kainate. For example, no induction of Dkk-1 was detected in the hippocampus of low responder rats, in which seizures did not cause neuronal loss. Induction of Dkk-1 always anticipated neuronal death and was associated with a reduction in nuclear levels of beta-catenin, which reflects an ongoing inhibition of the canonical Wnt pathway. Intracerebroventricular injections of Dkk-1 antisense oligonucleotides (12 nmol/2 microL) substantially reduced kainate-induced neuronal damage, as did a pretreatment with lithium ions (1 mEq/kg, i.p.), which rescue the Wnt pathway by acting downstream of the Dkk-1 blockade. Taken collectively, these data suggest that an early inhibition of the Wnt pathway by Dkk-1 contributes to neuronal damage associated with temporal lobe epilepsy. We also examined Dkk-1 expression in the hippocampus of epileptic patients and their controls. A strong Dkk-1 immunolabeling was found in six bioptic samples and in one autoptic sample from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Dkk-1 expression was undetectable or very low in autoptic samples from nonepileptic patients or in bioptic samples from patients with complex partial seizures without neuronal loss and/or reactive gliosis in the hippocampus. Our data raise the attractive possibility that drugs able to rescue the canonical Wnt pathway, such as Dkk-1 antagonists or inhibitors of glycogen synthase kinase-3beta, reduce the development of hippocampal sclerosis in patients with temporal lobe epilepsy.
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PMID:Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. 1743 12

Choroidal neovascularization (CNV) in age-related macular degeneration is a leading cause of blindness. Very low density lipoprotein receptor gene knock-out (Vldlr(-/-)) mice have been shown to develop subretinal neovascularization (NV) with an unknown mechanism. The present study showed that in Vldlr(-/-) mice, NV initiated in the choroid and progressed to penetrate the retinal pigment epithelium layer, proliferating in the subretinal space. This phenotype recapitulated what is seen in wet age-related macular degeneration, suggesting that this is a CNV model. The CNV correlated with overexpression of vascular endothelial growth factor in Vldlr(-/-) eyecups and was blocked by a neutralizing antibody against vascular endothelial growth factor receptor-2. The wnt co-receptor LRP5/6 expression was significantly up-regulated in Vldlr(-/-) eyecups compared with that in wild-type mice. Significantly, Vldlr(-/-) mice showed impaired phosphorylation of downstream effectors of the wnt signaling pathway, glycogen synthase kinase-3beta (GSK-3beta), and beta-catenin, concomitant with increased levels of free GSK-3beta and beta-catenin, suggesting an increased activity of the wnt pathway. Down-regulation of VLDLR by small interference RNA resulted in up-regulation of LRP5/6 expression and activation of beta-catenin in cultured endothelial cells. Furthermore, Dickkopf-1, a specific inhibitor of the wnt pathway, effectively decreased vascular endothelial growth factor and beta-catenin levels in the retinal pigment epithelium of Vldlr(-/-) mice and in cells transfected with the VLDLR small interference RNA. These results suggest that VLDLR functions as a negative regulator of CNV, and this function is mediated through the wnt pathway.
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PMID:Very low density lipoprotein receptor, a negative regulator of the wnt signaling pathway and choroidal neovascularization. 1789 Jul 82

Although the intermittent administration of PTH is known to stimulate the bone formation, the underlying mechanisms are not fully understood. Here we investigated the crosstalk between PTH/cAMP signaling and canonical Wnt signaling using the human osteoblastic cell line Saos-2. Treatment with PTH or forskolin, an activator of adenylate cyclase, facilitated T-cell factor (TCF)-dependent transactivation in a dose-dependent manner, which was abolished by pre-treatment with a PKA inhibitor, H89. Wnt3a and forskolin synergistically increased the TCF-dependent transactivation. Interestingly, intermittent treatment with PTH enhanced the TCF-dependent transactivation more profoundly than continuous treatment. In addition to the effects on TCF-dependent reporter activity, treatment with PTH or forskolin resulted in the increased expression of endogenous targets of Wnts, Wnt-induced secreted protein 2 (WISP2) and naked cuticle 2 (NKD2). We then investigated the convergence point of PTH/cAMP signaling and the canonical Wnt pathway. Western blotting demonstrated that GSK-3beta was rapidly phosphorylated at Ser(9) on treatment with PTH or forskolin, leading to its inactivation. Moreover, overexpression of a constitutively active mutant of GSK-3beta abolished the TCF-dependent transactivation induced by forskolin. On the other hand, overexpression of the Wnt antagonist Dickkopf-1 (DKK1) failed to cancel the effects of forskolin on the canonical Wnt pathway. Interestingly, treatment with Wnt3a markedly reduced the forskolin-induced expression of receptor activator of NF-kappaB ligand (RANKL), a target gene of PTH/cAMP/PKA. These results suggest that cAMP/PKA signaling activates the canonical Wnt pathway through the inactivation of GSK-3beta, whereas Wnt signaling might inhibit bone resorption through a negative impact on RANKL expression in osteoblasts.
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PMID:PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. 1799 Feb 94


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