Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic mechanisms responsible for increased incidence of lymphoma in immunocompromised individuals have not been fully elucidated. We show that, in a line of TCR transgenic TG-B mice, an insertional mutation in one allele of the Epm2a locus and epigenetic silencing of another led to a high rate of lymphoma with early onset. Overexpressing Epm2a suppressed the growth of established tumor cells and the development of lymphoma in the TG-B mice, while specific silencing of the locus increased tumorigenesis in the immune-deficient host. Downregulation of Epm2a expression is widespread among mouse and human lymphoma cell lines. Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway. Inactivation of Epm2a resulted in increased Wnt signaling and tumorigenesis.
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PMID:Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling. 1695 10

Adiponectin is an adipokine that has pleiotropic beneficial roles in systemic insulin resistance and inflammation. Several recent clinical studies suggest that low serum levels of adiponectin are associated with increased risks of breast cancer. Here, we investigated the direct effects of adiponectin on breast cancer development in vitro and in vivo. Our results showed that adiponectin significantly attenuated the proliferations of two typical human breast cancer cells, MDA-MB-231 and T47D, in a cell type-specific manner. Further analysis revealed that adiponectin could induce apoptosis and arrest the cell cycle progression at G(0)-G(1) phase in MDA-MB-231 cells. Prolonged treatment with adiponectin in this cell line blocked serum-induced phosphorylation of Akt and glycogen synthase kinase-3beta (GSK-3beta), suppressed intracellular accumulation of beta-catenin and its nuclear activities, and consequently reduced expression of cyclin D1. Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3beta inhibitor lithium chloride. These results suggest that the inhibitory role of adiponectin on MDA-MB-231 cell growth might be attributed to its suppressive effects on the GSK-3beta/beta-catenin signaling pathway. Furthermore, our in vivo study showed that both supplementation of recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice. Taken together, these data support the role of adiponectin as a negative regulator of breast cancer development and also suggest that adiponectin might represent a novel therapeutic target for this disease.
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PMID:Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. 1714 94

Rho GTPases regulate a multitude of cellular processes from cytoskeletal reorganization to gene transcription and are negatively regulated by GTPase-activating proteins (GAPs). Cdc42 GTPase-activating protein (CdGAP) is a ubiquitously expressed GAP for Rac1 and Cdc42. In this study, we set out to identify CdGAP-binding partners and, using a yeast two-hybrid approach, glycogen synthase kinase 3alpha (GSK-3alpha) was identified as a partner for CdGAP. GSK-3 exists in two isoforms, alpha and beta, and is involved in regulating many cellular functions from insulin response to tumorigenesis. We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. We report that the mRNA and protein levels of CdGAP are increased upon serum stimulation and that GSK-3 activity is necessary for the up-regulation of the protein levels of CdGAP but not for the increase in mRNA. We conclude that GSK-3 is an important regulator of CdGAP and that regulation of CdGAP protein levels by serum presents a novel mechanism for cells to control Cdc42/Rac1 GTPase signaling pathways.
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PMID:Glycogen synthase kinase-3 phosphorylates CdGAP at a consensus ERK 1 regulatory site. 1715 47

Aneuploidy occurs early during tumorigenesis and may contribute to tumor formation. Tumor cells become aneuploid as a result of aberrant mitotic divisions, suggesting a tumorigenic contribution of the mechanisms in maintaining chromosomal number stability. We therefore speculated that the genes TTK, MAD2L1, BUB1, BUB1B and PTTG1 (Securin), jointly implicated in the regulation of mitotic checkpoint, might be associated with breast tumorigenesis. To test this hypothesis, this case-control study of 698 primary breast cancer patients and 1492 healthy controls examined single-nucleotide polymorphisms (SNPs) in these mitotic checkpoint genes to define their tumorigenic contribution. Because estrogen is known to promote breast cancer development via its mitogenic effect leading to malignant proliferation of breast epithelium and the mitotic checkpoint genes are involved in regulating mitosis, we were also interested in knowing whether any association between genotypes and breast cancer risk was modified by reproductive risk factors. Support for these hypotheses came from the observations that (i) two SNPs in TTK and PTTG1 were associated with breast cancer risk; (ii) haplotype and haplotype combination analyses in TTK, BUB1B and PTTG1 revealed a strong association with breast cancer risk; (iii) a trend to an increased risk of breast cancer was found in women harboring a greater number of putative high-risk genotypes/haplotypes of mitotic checkpoint genes and (iv) a significant interaction between high-risk genotypes/haplotypes and reproductive risk factors in determining breast cancer risk was defined. This study provides new support for the mutator role of mitotic checkpoint genes in breast cancer development, suggesting that breast cancer could be driven by genomic instability associated with variant mitotic checkpoint genes, the tumorigenic contribution of which could be enhanced as a result of increased mitosis due to estrogen exposure.
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PMID:Breast cancer risk associated with genotypic polymorphism of the mitotic checkpoint genes: a multigenic study on cancer susceptibility. 1721 Sep 94

Aneuploidy, an aberrant number of chromosomes, is a very common characteristic of many types of cancers, including tumors of the breast. There is increasing evidence that defects in the spindle assembly checkpoint, which controls correct chromosome segregation between two daughter cells, might contribute to tumorigenesis. In the present study we examined the effect of promoter and coding single nucleotide polymorphisms (SNPs) in six major spindle checkpoint genes (BUB1B, BUB3, CENPE, MAD2L1, MAD2L2, TTK) on familial breast cancer (BC) risk. A case-control study was carried out with a total of nine SNPs using 441 German, familial BC cases and 552 controls matched by age, ethnicity and geographical region. Neither the individual SNPs in the studied genes nor the haplotypes in the BUB1B, CENPE and TTK genes caused any significant effect on the risk of BC. We used the multifactor-dimensionality reduction method in order to identify gene-gene interactions among the six mitotic checkpoint genes, but no association was detected. Therefore, our results indicate that the investigated SNPs in the mitotic checkpoint genes do not affect the risk of familial BC.
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PMID:Genetic variation in the major mitotic checkpoint genes does not affect familial breast cancer risk. 1726 14

Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization.
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PMID:Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. 1738 46

PRL-3 is a metastasis-associated phosphatase. We and others have shown that its overexpression increases cell motility and invasiveness. These phenotypic changes are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development and oncogenesis. The EMT is a complex process that converts epithelia into migratory mesenchymal cells. We here attempt to unravel the underlying mechanistic basis of these phenomena. HeLa cells transiently expressing EGFP-PRL-3 (HeLa-PRL-3) exhibit reduced levels of paxillin. Similarly, Chinese hamster ovary cells stably expressing myc-PRL-3 (CHO-PRL-3) also show marked reductions in paxillin, phosphorylated paxillin-Tyr(31), and vinculin at focal adhesion complexes and notable reductions in the levels of RhoA-GTP, Rac1-GTP, and filamentous-actin filaments. DLD-1 human colorectal cancer cells engineered to express EGFP-PRL-3 (DLD-1-PRL-3) underwent changes consistent with EMT. In these cells, PRL-3 activates Akt and inactivates glycogen synthase kinase-3beta as assessed by phosphospecific antibodies. PRL-3 up-regulates mesenchymal markers fibronectin and Snail and down-regulates epithelial markers E-cadherin, gamma-catenin (plakoglobin), and integrin beta(3), which are major effectors in the EMT pathway. The changes in these EMT characteristics brought about by PRL-3 can be abrogated by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, implying that PRL-3 acts upstream of PI3K and could play an initiating role to trigger the EMT switch during cancer metastasis. In addition, PRL-3 can down-regulate phosphatase and tensin homologue deleted on chromosome 10, which is an important antagonist of PI3K, further reinforcing PI3K/Akt function in PRL-3-triggered EMT. Catalytically inactive PRL-3 (C104S) was impaired in the above PRL-3-mediated events, indicating that these properties require phosphatase activity. Targeting PRL-3 may thus be a useful strategy to impede cancer cell invasion and metastasis.
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PMID:PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. 1740 95

Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3beta (GSK3beta) through Janus kinase2-dependent activation of phosphatidylinositol 3'-kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3beta and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3beta or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.
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PMID:Glycogen synthase kinase-3beta and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells. 1748 76

Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer and associates with cell immortalization, malignant transformation, and chemoresistance. Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3beta (p-GSK-3beta) at Ser(9) (an inactivated form of GSK-3beta) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-3beta could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3beta. Our results indicate that Mcl-1 stabilization by GSK-3beta inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
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PMID:Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. 1749 24

Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted.
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PMID:Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice. 1751 Jun 31


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