GSK J4 HCl - CAS 1373423-53-0
Catalog number: 1373423-53-0
Category: Inhibitor
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Histone Demethylase
GSK J4 HCl is a cell permeable prodrug of GSK J1, which is the first selective inhibitor of the H3K27 histone demethylase JMJD3 and UTX with IC50 of 60 nM and inactive against a panel of demethylases of the JMJ family.
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1.Histone H3 lysine 27 trimethylation acts as an epigenetic barrier in porcine nuclear reprogramming.
Xie B;Zhang H;Wei R;Li Q;Weng X;Kong Q;Liu Z Reproduction. 2016 Jan;151(1):9-16. doi: 10.1530/REP-15-0338. Epub 2015 Oct 29.
Aberrant epigenetic reprogramming is the main obstacle to the development of somatic cell nuclear transfer (SCNT) embryos and the generation of induced pluripotent stem (iPS) cells, which results in the low reprogramming efficiencies of SCNT and iPS. Histone H3 lysine 27 trimethylation (H3K27me3), as a repressive epigenetic mark, plays important roles in mammalian development and iPS induction. However, the reprogramming of H3K27me3 in pig remains elusive. In this study, we showed that H3K27me3 levels in porcine early cloned embryos were higher than that in IVF embryos. Then GSK126 and GSK-J4, two small molecule inhibitors of H3K27me3 methylase (EZH2) and demethylases (UTX/JMJD3), were used to regulate the H3K27me3 level. The results showed that H3K27me3 level was reduced in cloned embryos after treatment of PEF with 0.75 μM GSK126 for 48 h, incubation of one-cell reconstructed oocytes with 0.1 μM GSK126 and injection of antibody for EZH2 into oocyte. Meanwhile, the development of the cloned embryos was significantly improved after these treatments. On the contrary, GSK-J4 treatment increased the H3K27me3 level in cloned embryos and decreased the cloned embryonic development. Furthermore, iPS efficiency was both increased after reducing the H3K27me3 level in donor cells and in early reprogramming phase.
2.Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.
Jia W;Wu W;Yang D;Xiao C;Su Z;Huang Z;Li Z;Qin M;Huang M;Liu S;Long F;Mao J;Liu X;Zhu YZ FASEB J. 2018 Jul;32(7):4031-4042. doi: 10.1096/fj.201701483R. Epub 2018 Feb 26.
Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration.
3.Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function.
Backe MB;Andersson JL;Bacos K;Christensen DP;Hansen JB;Dorosz JJ;Gajhede M;Dahlby T;Bysani M;Kristensen LH;Ling C;Olsen L;Mandrup-Poulsen T Mol Cell Endocrinol. 2018 Jan 15;460:47-56. doi: 10.1016/j.mce.2017.07.001. Epub 2017 Jul 4.
Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated.
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CAS 1373423-53-0 GSK J4 HCl

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