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)

Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and beta-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and beta-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and beta-catenin.
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PMID:GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity. 1169 57

We have isolated the entire coding sequence of human FRAT2 (frequently rearranged in advanced T-cell lymphomas-2). It exhibits appreciable amino acid identity to FRAT1 (77%) which was initially isolated as frequently being overexpressed in a murine leukemia virus insertion model in murine tumors. FRAT proteins are thought to play a role in Wnt signaling. They can bind to glycogen synthase kinase-3 (GSK-3) and Dishevelled, two proteins involved in Wnt signal transduction. Both hFRAT1 and hFRAT2 are intronless genes localized to the same portion of chromosome 10q24.1 and separated by only 10.7 kb. In a broad range of human tissues FRAT1 and FRAT2 are readily detected and expressed in a near identical pattern. Both species are repressed when the human embryonal carcinoma cell line, NT2/D1, is induced to differentiate with all-trans retinoic acid (RA). This treatment had no appreciable effect on FRAT levels in two other RA-sensitive cell lines that were not of germ cell tumor origin. The overlapping expression patterns suggest these two genes share a regulatory region. Both FRAT genes exhibited three species of mRNA, which varied in representation between tissues. When transiently overexpressed in COS-1 cells, the FRAT proteins were detected in the cytosol and concentrated in the nucleus. Both hFRAT1 and hFRAT2 are implicated in the selective modulation of GSK-3 activity via the Wnt signaling pathway. This study provides a foundation from which to examine the role these proteins play in Wnt-dependent and -independent processes.
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PMID:Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2. 1209 75

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Although aberrant activation of beta-catenin/T-cell factor (TCF) pathway has been observed in ESCC, mechanisms underlying this phenomenon remain unknown. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1), overexpressed in some ESCC lines, is a positive regulator of beta-catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and beta-catenin/TCF in ESCC. In this study, we analyzed freshly resected ESCC specimens and demonstrated that FRAT1 was overexpressed in approximately 74% of tumor samples compared with matched normal tissue. Overexpression of FRAT1 significantly promoted esophageal cancer cells growth, whereas suppression of FRAT1 level by RNAi markedly inhibited their growth. In addition, FRAT1 overexpression induced the nuclear accumulation of beta-catenin and promoted the transcriptional activity of beta-catenin/TCF. These effects were reversed by coexpression of GSK 3beta or DeltaN TCF4. Furthermore, accumulation of beta-catenin was correlated with FRAT1 overexpression in ESCC and the basal layer of normal esophageal epithelium. Finally, continued expression of c-Myc is necessary and sufficient for maintenance of the growth state in cells expressing FRAT1. Taken together, these results support the novel hypothesis that aberrant activation of beta-catenin/TCF pathway in esophageal cancer appears to be due to upstream events such as FRAT1 overexpression, and c-Myc may be an important element in oncogenesis of human ESCC induced by FRAT1.
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PMID:FRAT1 overexpression leads to aberrant activation of beta-catenin/TCF pathway in esophageal squamous cell carcinoma. 1849 36