NGF-Induced Axon Growth Is Mediated by Localized Inactivation of GSK-3β and Functions of the Microtubule Plus End Binding Protein APC

Mastoparan B (MP-B), a cationic tetradecapeptide isolated from the venom of the Vespa basalis, exhibits cardiovascular effects, local edema and antibacterial activity. In this study, the anti-adipogenic effect of an MP-B analogue and its mechanism of action in 3T3-L1 preadipocytes were studied. The MP-B analogue (MP-B12) inhibited preadipocyte differentiation and decreased the expression of adipogenic transcription factors, including CCAAT/enhancer binding protein-alpha (C/EBPα), nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, MP-B12 regulated the phosphorylation of Akt and glycogen synthase kinase-3 beta (GSK-3β), both of which play a role in preadipocyte differentiation, in which insulin and certain growth factors stimulated adipogenesis. This study demonstrates that MP-B12 inhibits preadipocyte differentiation and the accumulation of lipid droplets in 3T3-L1 preadipocytes and could potentially be used to treat obesity.Video Clip of Methodology:4 min 11 sec Full Screen Alternate

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The transcriptional corepressor TPA-inducible sequence 7 regulates adult axon growth through cellular retinoic acid binding protein II expression

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2007.05951.x ◽

2007 ◽

Vol 26 (12) ◽

pp. 3358-3367 ◽

Cited By ~ 5

Author(s):

Benjamin Dieplinger ◽

Natalia Schiefermeier ◽

Michaela Juchum-Pasquazzo ◽

Ronald Gstir ◽

Lukas A. Huber ◽

...

Keyword(s):

Retinoic Acid ◽

Binding Protein ◽

Axon Growth ◽

Transcriptional Corepressor ◽

Acid Binding Protein

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Xuebijing Protects Against Septic Acute Liver Injury Based on Regulation of GSK-3β Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.627716 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liping Cao ◽

Zhenghong Li ◽

Yi Ren ◽

Mengmeng Wang ◽

Zhizhou Yang ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Glycogen Synthase ◽

Binding Protein ◽

Cecal Ligation ◽

Inflammatory Factors ◽

Dependent Manner ◽

Protective Effects ◽

Creb Binding Protein ◽

Gsk 3Β

Xuebijing (XBJ), the only drug approved for the sepsis and multiple organ dysfunction, and its protective effects against acute liver injury (ALI) and its mechanism. The aim of this study was to evaluate the protective effect of XBJ on cecal ligation and perforation (CLP)-induced mouse ALI model and LPS-induced RAW264.7 cell ALI model. Mice were pretreated with XBJ before the CLP model was established, and serum and liver tissues were collected at the end of the experiment to assess the levels of inflammatory factors and liver injury. Results showed that XBJ pretreatment reduced liver/body weight, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum, and inhibited levels of pro-inflammatory factors in serum. Cells were treatment with XBJ and modeled by LPS modeling increased cell viability in the XBJ-treated group compared to the model group and XBJ also decreased serum pro-inflammatory factors in a dose-dependent manner. Western blot detected that XBJ also up-regulated the phosphorylated levels of glycogen synthase kinase-3β (p-GSK-3β) and cAMP-response element-binding protein (p-CREB) and down-regulated the phosphorylated level of nuclear factor kappa-B (p-NF-κB) in liver and cell. After overexpression of GSK-3β in cells, the mechanism was further investigated using CO-IP analysis. The binding of p-NF-κB and p-CREB to CREB-binding protein (CBP) was increased and decreased, respectively, indicating that GSK-3β regulated inflammation by regulating the binding of p-NF-κB and p-CREB to CBP. The present studies suggested that the hepatoprotective effect of XBJ may be through up-regulation of GSK-3β (Ser9) and increasing the binding of p-CREB to CBP, thereby alleviating the inflammatory response.

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GSK-3β at the Crossroads in Regulating Protein Synthesis and Lipid Deposition in Zebrafish

Cells ◽

10.3390/cells8030205 ◽

2019 ◽

Vol 8 (3) ◽

pp. 205 ◽

Cited By ~ 3

Author(s):

Yaqi Gu ◽

Lili Gao ◽

Qiang Han ◽

Ao Li ◽

Hairui Yu ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Expression ◽

Danio Rerio ◽

Fatty Acid Synthase ◽

Binding Protein ◽

Lipid Deposition ◽

Nonesterified Fatty Acids ◽

Mrna And Protein Expression ◽

Ribosomal S6 Kinase ◽

Gsk 3Β

In this study, the mechanism by which GSK-3β regulates protein synthesis and lipid deposition was investigated in zebrafish (Danio rerio). The vector of pEGFP-N1-GSK-3β was constructed and injected into the muscle of zebrafish. It was found that the mRNA and protein expression of tuberous sclerosis complex 2 (TSC2) was significantly increased. However, the mRNA and protein expression of mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (S6K1), and 4E-binding protein 1 (4EBP1) was significantly decreased by the pEGFP-N1-GSK-3β vector in the muscle of zebrafish. In addition, the mRNA and protein expression of β-catenin, CCAAT/enhancer binding protein α (C/EBPα), and peroxisome proliferators-activated receptor γ (PPARγ) was significantly decreased, but the mRNA expression of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), ATP-citrate lyase (ACL), and HMG-CoA reductase (HMGCR) was significantly increased by the pEGFP-N1-GSK-3β vector. The activity of FAS, ACC, ACL, and HMGCR as well as the content of triglyceride (TG), total cholesterol (TC), and nonesterified fatty acids (NEFA) were significantly increased by the pEGFP-N1-GSK-3β vector in the muscle of zebrafish. The content of free amino acids Arg, Lys, His, Phe, Leu, Ile, Val, and Thr was significantly decreased by the pEGFP-N1-GSK-3β vector. The results indicate that GSK-3β may participate in regulating protein synthesis via TSC2/mTOR signaling and regulating lipid deposition via β-catenin in the muscle of zebrafish (Danio rerio).

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The Inositol Polyphosphate 5-Phosphatase, PIPP, Is a Novel Regulator of Phosphoinositide 3-Kinase-dependent Neurite Elongation

Molecular Biology of the Cell ◽

10.1091/mbc.e05-05-0469 ◽

2006 ◽

Vol 17 (2) ◽

pp. 607-622 ◽

Cited By ~ 51

Author(s):

Lisa M. Ooms ◽

Clare G. Fedele ◽

Megan V. Astle ◽

Ivan Ivetac ◽

Vanessa Cheung ◽

...

Keyword(s):

Pc12 Cells ◽

Growth Cone ◽

Molecular Mechanisms ◽

Axon Growth ◽

Pi3 Kinase ◽

Inositol Polyphosphate ◽

Neurite Elongation ◽

Microtubule Polymerization ◽

Gsk 3Β ◽

Phosphoinositide 3 Kinase

The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilitates Akt activation and stimulates GSK-3β inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyperelongation. Inhibition of PI3-kinase activity prevented neurite hyperelongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3β, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3β signaling.

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Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish

Cells ◽

10.3390/cells9051238 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1238

Author(s):

Doris Lou Demy ◽

Maria Letizia Campanari ◽

Raphael Munoz-Ruiz ◽

Heather D. Durham ◽

Benoit J. Gentil ◽

...

Keyword(s):

Motor Neurons ◽

Rna Binding ◽

De Novo ◽

Binding Protein ◽

Functional Characterization ◽

Axon Growth ◽

Motor Deficits ◽

Neurofilament Light ◽

Cytoplasmic Inclusions

Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in the differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit (NEFL), whose expression is reduced in motor neurons in amyotrophic lateral sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via a splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects the NF assembly and motor axon growth, with resultant motor deficits. This equilibrium is also disrupted upon the partial depletion of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the gene TARDBP that is mislocalized into cytoplasmic inclusions in ALS. The study supports the interaction of the NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

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Intracellular control of developmental and regenerative axon growth

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2006.1882 ◽

2006 ◽

Vol 361 (1473) ◽

pp. 1575-1592 ◽

Cited By ~ 117

Author(s):

Feng-Quan Zhou ◽

William D Snider

Keyword(s):

Gene Expression ◽

Growth Factors ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Glycogen Synthase ◽

Axon Growth ◽

Protein Translation ◽

Activated T Cells ◽

Local Assembly ◽

Gsk 3Β

Axon growth is a highly regulated process that requires stimulating signals from extracellular factors. The extracellular signals are then transduced to regulate coordinately gene expression and local axon assembly. Growth factors, especially neurotrophins that act via receptor tyrosine kinases, have been heavily studied as extracellular factors that stimulate axon growth. Downstream of receptor tyrosine kinases, recent studies have suggested that phosphatidylinositol-3 kinase (PI3K) regulates local assembly of axonal cytoskeleton, especially microtubules, via glycogen synthase kinase 3β (GSK-3β) and multiple microtubule binding proteins. The role of extracellular signal regulated kinase (ERK) signalling in regulation of local axon assembly is less clear, but may involve the regulation of local protein translation. Gene expression during axon growth is regulated by transcription factors, among which cyclic AMP response element binding protein and nuclear factors of activated T-cells (NFATs) are known to be required for neurotrophin (NT)-induced axon extension. In addition to growth factors, extracellular matrix molecules and neuronal activity contribute importantly to control axon growth. Increasingly, evidence suggests that these influences act to enhance growth via coordinating with growth factor signalling. Finally, evidence is emerging that developmental versus regenerative axon growth may be mediated by distinct signalling pathways, both at the level of gene transcription and at the level of local axon assembly.

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