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Sandra G Gonzalez Malagon, Anna M Lopez Muñoz, Daniel Doro, Triòna G Bolger, Evon Poon, Elizabeth R Tucker, Hadeel Adel Al-Lami, Matthias Krause, Christopher J Phiel, Louis Chesler, Karen J Liu
Neural crest migration is critical to its physiological function. Mechanisms controlling mammalian neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here we report requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest in Xenopus and mouse models. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in mouse neural crest cells and that loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration...
March 19, 2018: Nature Communications
Florence F Wagner, Lina Benajiba, Arthur J Campbell, Michel Weïwer, Joshua R Sacher, Jennifer P Gale, Linda Ross, Alexandre Puissant, Gabriela Alexe, Amy Conway, Morgan Back, Yana Pikman, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Taner Kaya, Xi Shi, Matthew B Robers, Thomas Machleidt, Jennifer Wilkinson, Olivier Hermine, Andrew Kung, Adam J Stein, Damodharan Lakshminarasimhan, Michael T Hemann, Edward Scolnick, Yan-Ling Zhang, Jen Q Pan, Kimberly Stegmaier, Edward B Holson
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers...
March 7, 2018: Science Translational Medicine
Mohsen Sarikhani, Sneha Mishra, Sangeeta Maity, Chaithanya Kotyada, Donald Wolfgeher, Mahesh P Gupta, Mahavir Singh, Nagalingam R Sundaresan
Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3α and GSK3β are acetylated at Lys246 and Lys183 respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates...
March 5, 2018: ELife
Diane M Sepa-Kishi, Glen Katsnelson, George Bikopoulos, Ayesha Iqbal, Rolando B Ceddia
This study investigated the molecular and metabolic responses of the liver to cold-induced thermogenesis. To accomplish that, male Wistar rats were exposed to cold (4°C) for 7 days. Livers were then extracted and used for the determination of glucose and fatty acid oxidation, glycogen content, the expression and content of proteins involved in insulin signaling, as well as in the regulation of gluconeogenesis and de novo lipid synthesis. Despite being hyperphagic, cold-acclimated rats displayed normoglycemia with reduced insulinemia, which suggests improved whole-body insulin sensitivity...
March 2018: Physiological Reports
Weihai Liu, Zhiqiang Zhao, Yongqian Wang, Wuguo Li, Qiao Su, Qiang Jia, Jiajun Zhang, Xuelin Zhang, Junqiang Yin, Jingnan Shen
Osteosarcoma is the most common primary bone tumor in children and adolescents. Many patients with osteosarcoma always develop drug resistance to current chemotherapy regimens, which induces a poor prognosis. And cancer stem cells (CSCs) have been reported to possess the properties to self-renew and maintain the phenotype of tumor, which may lead to clinical treatment failure. Thus, it is an urgent task to develop several potentially useful therapeutic agents, which could target CSCs in osteosarcoma. This study aims to clarify the in vitro and in vivo anti-osteosarcoma effects of dioscin, the primary component derived from Discorea nipponica Makino, and its molecular mechanism of action...
March 1, 2018: Cell Death & Disease
Sandeep R Kunati, Shuming Yang, David Wald, Yan Xu
GS87 is a novel, highly specific GSK3 inhibitor, which has shown to induce extensive differentiation of acute myeloid leukemia (AML) cells in early mouse studies and has great potential for therapeutic advancement. This work described the development and validation of an LC-MS/MS method for quantitative determination of GS87 in mouse plasma. In this method, GS87 and T6447952 (a structural analog used as internal standard) were extracted from plasma using hexane as extraction solvent, and separated isocratically on a Waters XTerra® MS C8 column (2...
February 19, 2018: Journal of Pharmaceutical and Biomedical Analysis
Lasse K Markussen, Sally Winther, Barton Wicksteed, Jacob B Hansen
Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes...
February 22, 2018: Scientific Reports
Yuyan Cheng, Sachi Desse, Ana Martinez, Ryan J Worthen, Richard S Jope, Eleonore Beurel
Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5...
February 13, 2018: Brain, Behavior, and Immunity
Haoming Zhou, Han Wang, Ming Ni, Shi Yue, Yongxiang Xia, Ronald W Busuttil, Jerzy W Kupiec-Weglinski, Ling Lu, Xuehao Wang, Yuan Zhai
BACKGROUND & AIMS: Glycogen synthase kinase 3β (Gsk3β) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischemia and reperfusion injuries (IRI) have been well documented, underlying mechanisms remain ambiguous, due in part to the lack of cell-specific tools in vivo. METHODS: We created a myeloid-specific Gsk3β KO strain to study its function in macrophages in a murine liver partial warm ischemia model...
February 13, 2018: Journal of Hepatology
Monalisa Ribeiro Silva, Alyne Oliveira Correia, Gabriel Cabral Alencar Dos Santos, Lucas Leimig Telles Parente, Keicy Parente de Siqueira, Danielly Gonçalves Sombra Lima, Jonathan Almeida Moura, Ana Elisa da Silva Ribeiro, Roberta Oliveira Costa, Daniel Luna Lucetti, Elaine Cristina Pereira Lucetti, Kelly Rose Tavares Neves, Glauce Socorro de Barros Viana
Valproic acid (VA) is an antiepileptic that is also used for the treatment of bipolar disorders. The objective was to evaluate the neuroprotective effects of VA on a brain ischemia model. The groups of male Wistar rats were: SO (sham-operated), ischemic and ischemic treated with VA (25, 50 and 100 mg/kg, p.o.). After anesthesia with ketamine and xilazine, the animals were subjected to clamping of carotid arteries (30 min) and reperfusion. Except for the carotid clamping, the SO group was submitted to the same procedure...
February 13, 2018: Pharmacology, Biochemistry, and Behavior
Octavio Silva-García, Rosa Rico-Mata, María Cristina Maldonado-Pichardo, Alejandro Bravo-Patiño, Juan J Valdez-Alarcón, Jorge Aguirre-González, Víctor M Baizabal-Aguirre
Glycogen synthase kinase 3 (GSK3) is a constitutive enzyme implicated in the regulation of cytokine expression and the inflammatory response during bacterial infections. Mammals have two GSK3 isoforms named GSK3α and GSK3β that plays different but often overlapping functions. Although the role of GSK3β in cytokine regulation during the inflammatory response caused by bacteria is well described, GSK3α has not been found to participate in this process. Therefore, we tested if GSK3α may act as a regulatory isoform in the cytokine expression by bovine endothelial cells infected with Staphylococcus aureus because this bacterium is one of the major pathogens that cause tissue damage associated with inflammatory dysfunction...
2018: Frontiers in Immunology
Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines, Charles D Smith
Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate vital cellular functions such as proliferation, apoptosis and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy...
February 6, 2018: Journal of Pharmacology and Experimental Therapeutics
Tao Shu, Chang Liu, Mao Pang, Lei He, Bu Yang, Lei Fan, Shufan Zhang, Xuan Wang, Bin Liu, Limin Rong
Salvianolic acid B (Sal B), a water-soluble component mainly extracted from the traditional Chinese medicine Salvia miltiorrhiza, has potential anti-inflammatory, anti-oxidative and anti-apoptotic actions to protect neural cells. Here, we explore the effects and mechanisms of Sal B on the promotion of differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), then further into neurons. During the processes of neural differentiation of iPSCs, Sal B or a phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002) were added to the medium...
February 5, 2018: Neuroscience Letters
Brent D Aulston, Jason Shapansky, YaWen Huang, Gary L Odero, Gordon W Glazner
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals...
February 2, 2018: Experimental Neurology
Ofelia Tacchelly-Benites, Zhenghan Wang, Eungi Yang, Hassina Benchabane, Ai Tian, Michael P Randall, Yashi Ahmed
The aberrant activation of Wnt signal transduction initiates the development of 90% of colorectal cancers, the majority of which arise from inactivation of the tumor suppressor Adenomatous polyposis coli (APC). In the classical model for Wnt signaling, the primary role of APC is to act, together with the concentration-limiting scaffold protein Axin, in a "destruction complex" that directs the phosphorylation and consequent proteasomal degradation of the transcriptional activator β-catenin, thereby preventing signaling in the Wnt-off state...
February 2018: PLoS Genetics
Pamela J Windsor Reid, Eugueni Matveev, Alexandra McClymont, Dora Posfai, April L Hill, Sally P Leys
BACKGROUND: The Wnt signaling pathway is uniquely metazoan and used in many processes during development, including the formation of polarity and body axes. In sponges, one of the earliest diverging animal groups, Wnt pathway genes have diverse expression patterns in different groups including along the anterior-posterior axis of two sponge larvae, and in the osculum and ostia of others. We studied the function of Wnt signaling and body polarity formation through expression, knockdown, and larval manipulation in several freshwater sponge species...
February 2, 2018: BMC Evolutionary Biology
Rahul Bhattacharjee, Suranjana Goswami, Souvik Dey, Mahinda Gangoda, Cameron Brothag, Alaa Eisa, James Woodgett, Christopher Phiel, Douglas Kline, Srinivasan Vijayaraghavan
Glycogen synthase kinase 3 (GSK3) is a highly conserved protein kinase regulating key cellular functions. Its two isoforms, GSK3α and GSK3β, are encoded by distinct genes. In most tissues the two isoforms are functionally interchangeable, except in the developing embryo where GSK3β is essential. One functional allele of either of the two isoforms is sufficient to maintain normal tissue functions. Both GSK3 isoforms, present in sperm from several species including human, are suggested to play a role in epididymal initiation of sperm motility...
January 29, 2018: Biology of Reproduction
Andrew R Patterson, Mehari Endale, Kristin Lampe, Halil I Aksoylar, Aron Flagg, Jim R Woodgett, David Hildeman, Michael B Jordan, Harinder Singh, Zeynep Kucuk, Jack Bleesing, Kasper Hoebe
GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3β, thereby limiting DNA damage in CD4+ T cells...
January 30, 2018: Nature Communications
Jesus Lacal, Zhouxin Shen, Kimberly Baumgardner, Jing Wei, Steven P Briggs, Richard A Firtel
GSK3 plays a central role in orchestrating key biological signaling pathways, including cell migration. Here, we identify GlkA as a GSK3 family kinase with functions that overlap with and are distinct from those of GskA. We show that GlkA, as previously shown for GskA, regulates the cell's cytoskeleton through MyoII assembly and control of Ras and Rap1 function, leading to aberrant cell migration. However, there are both qualitative and quantitative differences in the regulation of Ras and Rap1 and their downstream effectors, including PKB, PKBR1, and PI3K, with glkA- cells exhibiting a more severe chemotaxis phenotype than gskA- cells...
January 16, 2018: Developmental Biology
Andrew Arner, Edward Rockenstein, Michael Mante, Jazmin Florio, Deborah Masliah, Bahar Salehi, Anthony Adame, Cassia Overk, Eliezer Masliah, Robert A Rissman
 Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology...
2018: Journal of Alzheimer's Disease: JAD
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