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 present study shows that the IFN-gamma-mediated upregulation of secretory phospholipase A2 of group IIA (sPLA2-IIA) in HASMC and HepG2 cells is synergistically increased after simultaneous inhibition of glycogen synthase kinase-3beta (GSK-3beta) by indirubin-3'-monoxime, 5-iodo or AR-A014418. The effect of GSK-3beta inhibition was dose- and time-dependent and can be further augmented by its concomitant incubation with Clostridium difficile toxin B, an inhibitor of small Rho proteins, or H-1152, an inhibitor of Rho-associated kinase. Using AG-490 and caffeic acid phenethyl ester (CAPE), it is further demonstrated that the effect of GSK-3beta inhibition on sPLA2-IIA expression depends on Janus kinase-2 and NF-kappaB-signaling.
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PMID:Glycogen synthase kinase-3beta negatively regulates group IIA phospholipase A2 expression in human aortic smooth muscle and HepG2 hepatoma cells. 1552 65

Myofibrillar protein loss occurring in catabolic situations is considered to be mediated by the release of proinflammatory cytokines and associated with a decrease in circulating and muscle levels of insulin-like growth factor I (IGF-I). In this paper, we investigated whether the C(2)C(12) myotube atrophy caused in vitro by TNF-alpha/IFN-gamma cytokines might be reversed by exogenous IGF-I. Our results showed that, despite the presence of TNF-alpha/IFN-gamma, IGF-I retained its full ability to induce the phosphorylation of Akt, Foxo3a, and GSK-3beta (respectively, 16-fold, 9-fold, and 2-fold) together with a decrease in atrogin-1 mRNA (-39%, P < 0.001). Although this ubiquitin ligase has been reported to accelerate the degradation of MyoD, a myogenic transcription factor driving the transcription of myosin heavy chain (MHC), IGF-I failed to blunt the reduction of MyoD and MHC caused by TNF-alpha/IFN-gamma. Moreover, IGF-I only very slightly attenuated the myotube atrophy induced by TNF-alpha/IFN-gamma (TNF-alpha/IFN-gamma 15.48 mum alone vs. TNF-alpha/IFN-gamma/IGF-I 16.97 mum, P < 0.001). In conclusion, our data show that IGF-I does not reverse the myotube atrophy induced by TNF-alpha/IFN-gamma despite the phosphorylation of Foxo and GSK-3beta and the downregulation of atrogin-1 mRNA. Our study suggests therefore that factors other than IGF-I decrease are responsible for the muscle atrophy caused by proinflammatory cytokines.
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PMID:IGF-I does not prevent myotube atrophy caused by proinflammatory cytokines despite activation of Akt/Foxo and GSK-3beta pathways and inhibition of atrogin-1 mRNA. 1692 85

The receptor-binding domain of Plasmodium vivax Duffy-binding protein, region II (PvRII), is an attractive candidate for a vaccine against P. vivax malaria. Here, we have studied the safety and immunogenicity of recombinant PvRII in Macaca mulatta (rhesus monkeys). Recombinant PvRII with a C-terminal 6-histidine tag was expressed in E. coli, recovered from inclusion bodies, refolded into its functional conformation, purified to homogeneity and formulated with three adjuvants, namely, Alhydrogel, Montanide ISA 720 and the GSK proprietary Adjuvant System AS02A for use in immunogenicity studies. All the PvRII vaccine formulations tested were safe and highly immunogenic. The overall magnitude of the antibody response was significantly higher for both Montanide ISA 720 and AS02A formulations in comparison with Alhydrogel. Furthermore, there was a significant correlation between antibody recognition titers by ELISA and binding inhibition titers in in vitro binding assays. The PvRII vaccine formulations also induced IFN-gamma recall responses that were identified using ex vivo ELISPOT assays. These results provide support for further clinical development of a vaccine for P. vivax malaria based on recombinant PvRII.
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PMID:Preclinical assessment of the receptor-binding domain of Plasmodium vivax Duffy-binding protein as a vaccine candidate in rhesus macaques. 1857 99

Glycogen synthase kinase-3beta (GSK-3beta)-modulated IFN-gamma-induced inflammation has been reported; however, the mechanism that activates GSK-3beta and the effects of activation remain unclear. Inhibiting GSK-3beta decreased IFN-gamma-induced inflammation. IFN-gamma treatment rapidly activated GSK-3beta via neutral sphingomyelinase- and okadaic acid-sensitive phosphatase-regulated dephosphorylation at Ser(9), and proline-rich tyrosine kinase 2 (Pyk2)-regulated phosphorylation at Tyr(216). Pyk2 was activated through phosphatidylcholine-specific phospholipase C (PC-PLC)-, protein kinase C (PKC)-, and Src-regulated pathways. The activation of PC-PLC, Pyk2, and GSK-3beta was potentially regulated by IFN-gamma receptor 2-associated Jak2, but it was independent of IFN-gamma receptor 1. Furthermore, Jak2/PC-PLC/PKC/cytosolic phospholipase A(2) positively regulated neutral sphingomyelinase. Inhibiting GSK-3beta activated Src homology-2 domain-containing phosphatase 2 (SHP2), thereby preventing STAT1 activation in the late stage of IFN-gamma stimulation. All these results showed that activated GSK-3beta synergistically affected IFN-gamma-induced STAT1 activation by inhibiting SHP2.
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PMID:Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. 1954 64