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  • Ikaros utilizes chromatin remodeling to activate


    Ikaros utilizes Z-VEID-FMK remodeling to activate or repress the transcription of its target genes (Su et al., 2004). Ikaros directly associates with histone deacetylases HDAC1 and HDAC2 and can recruit them to the upstream regulatory elements of its target genes (Kim et al., 1999, Koipally et al., 1999a, Koipally et al., 1999b). The ability of Ikaros to regulate transcription of its target genes is often dependent on its ability to localize to pericetromeric heterochromatin (Brown et al., 1997, Cobb et al., 2000, Liberg et al., 2003). Ikaros binds to the upstream regulatory element (URE) of its target genes and assists in their recruitment to pericentromeric heterochromatin (Brown et al., 1997).
    Conclusion The first mechanism involves direct phosphorylation of target proteins (phosphorylation of PTEN by CK2 and GSK-3). The second mechanism involves transcriptional regulation of PI3K-promoting genes (via CK2-mediated phosphorylation of Ikaros) (Fig. 1). The role of Ikaros in regulating the PI3K pathway illustrates a major distinction from the typical cross-talk between two signaling pathways that involves only posttranslational modifications of the same target proteins.
    Conflict of interest
    Acknowledgements This work has been supported by Hyundai Hope on Wheels Scholar Grant Award, Alex's Lemonade Stand Grant, Bear Necessities Pediatric Cancer Foundation, the Four Diamonds Fund of the Pennsylvania State University, College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (SD); by NIHR01 CA209829 (SD and KJP), by St. Baldrick's Foundation Fellows Award and Hyundai Hope on Wheels Fellowship Grant Award (CG).
    Introduction Glycogen Synthase Kinase-3 (GSK-3; EC No: has been named for its initial determined function of phosphorylating the target downstream enzyme glycogen synthase (GS), rendering the later inactive. GSK-3, a serine/threonine kinase, is currently found to have multiple actions, apart from the above mentioned initial activity, such as insulin signaling, glycogen metabolism, cellular proliferation, neuronal functions, apoptosis, embryonic development and oncogenesis to name a few. Thus, some of the GSK-3 targets involved in the above mentioned functions are Z-VEID-FMK glycogen synthase, tau protein (microtubule protein) and β-catenin. Due to these multivariant actions, the enzyme has been implicated in multiple diseases like Non Insulin Dependent Diabetes Mellitus (NIDDM), also known as Type 2 diabetes mellitus (T2DM), Alzheimer’s Disease (AD), certain Cancers and others [1], [2]. Physiologically, there are two mammalian isoforms of the enzyme GSK-3, namely GSK-3α (mol. wt. 51kDa) and GSK-3β (mol. wt. 47kDa). Among these isoforms, GSK-3β (EC No:, a 420 residue long enzyme, is the primary isoform regulating the GS activity and insulin signaling in muscle. (Fig. 1) One of the primary actions of insulin is conversion of blood glucose to glycogen and storage into the muscle cells. Insulin, on binding to insulin receptor, inhibits GSK-3β which in turn prevents phosphorylation and increases dephosphorylation of GS, keeping it active. The basic process involves activation of phosphoionositide-3 kinase (PI-3K), which activates its target PKB (or Akt) which in turn phosphorylates and inactivates GSK-3β. The enzyme GS plays the most crucial role in the synthesis of storage polysaccharide glycogen, muscle being the major storage site. Thus, conversion of blood glucose to muscle glycogen keeps the blood glucose level in control [3], [4]. It was demonstrated in animal model that tissue specific inhibition of GSK-3β (in liver and skeletal muscle) delivered different effects. While liver specific GSK-3β knockout (KO) mice showed normal metabolic features with no effect on glucose regulation, skeletal muscle GSK-3β KO mice showed improved glucose tolerance and better GS activation and glycogen storage [4]. Mussman et al. have shown that inhibition of GSK-3β also promotes proliferation and replication of pancreatic β-cells and preventing hyperglycemia and free fatty acid (FFA) induced cell death [5]. GSK-3 inhibition is primarily based on four preferred sites: ATP binding domain, Mg2+ binding domain, scaffold binding region and substrate binding domain. Most of the GSK-3 inhibitors being tested work by binding the ATP binding domain [6].