This document summarizes the bifunctional role of glycogen synthase kinase-3 beta (GSK-3β) in regulating cell death pathways. GSK-3β can both promote and inhibit apoptosis depending on cell type and signaling environment. It promotes apoptosis by inhibiting pro-survival factors and facilitating pro-apoptotic factors like p53. However, it also inhibits apoptosis under basal conditions by promoting degradation of p53 through MDM2 and stabilizing NF-κB, which protects against tumor necrosis factor-induced cell death. Due to its complex roles in cell survival, GSK-3β is an important target for drug development in diseases like cancer.
Genetic variations in G protein-coupled receptors (GPCRs) can alter receptor function and cause diseases. Single nucleotide polymorphisms and other mutations have been linked to impaired or enhanced receptor signaling. For example, a mutation in the vasopressin V2 receptor causes nephrogenic diabetes insipidus by decreasing ligand binding and receptor expression. Similarly, mutations in chemokine receptors CCR5 and CCR2 impact HIV infection by altering receptor function or interaction with other coreceptors. Overall, GPCR polymorphisms are associated with diseases by changing ligand binding, receptor activation, trafficking, and coupling to downstream signaling pathways.
This document summarizes a study examining how transforming growth factor beta (TGFβ) regulates expression of cysteine-rich protein 2 (CRP2) in vascular smooth muscle cells (VSMCs). The researchers found that TGFβ significantly induced CRP2 mRNA and protein expression in VSMCs. Promoter analysis identified a conserved cAMP-responsive element (CRE)-like site in the CRP2 promoter that was critical for basal promoter activity and response to TGFβ. Gel shift assays revealed that activating transcription factor 2 (ATF2) bound to this CRE-like element. TGFβ enhanced ATF2 phosphorylation and activation, leading to increased phospho-ATF2 levels and CRP2 promoter
This study investigated the role of histone H3 lysine 18 acetylation (H3K18ac) in maintaining pluripotency in embryonic stem cells. The researchers found that H3K18ac is highly enriched at stem cell genes in embryonic stem cells and levels decrease with differentiation. Expression of the E1A oncoprotein in mouse embryonic stem cells globally reduced H3K18ac and caused the cells to lose pluripotent characteristics, fail to activate stem cell enhancers, and suppress lineage-specific genes. Loss of pluripotency upon E1A expression required binding of E1A to the H3K18 acetyltransferases p300/CBP. This suggests H3K
MDM2 promotes the ubiquitination and degradation of FOXO transcription factors. The study found that MDM2 binds directly to FOXO1 and FOXO3A, promoting their ubiquitination and proteasome-mediated degradation. This degradation was dependent on FOXO phosphorylation by AKT and the E3 ligase activity of MDM2. Furthermore, activation of p53 led to increased MDM2 levels and degradation of endogenous FOXO3A. Therefore, MDM2 acts as an E3 ubiquitin ligase downstream of p53 to regulate FOXO protein stability.
1) The study investigates the role of b-catenin in myogenesis using P19 cells with reduced b-catenin activity (P19[shb-cat] cells) compared to control cells.
2) The loss of b-catenin resulted in reduced expression of genes involved in premyogenic mesoderm formation and skeletal myogenesis.
3) While retinoic acid could partially compensate by upregulating some precursor genes in P19[shb-cat] cells, it could not compensate for the expression of genes required for terminal myogenesis or overall skeletal muscle formation.
G-proteins are molecular switches that regulate various cellular activities. They exist in two classes: monomeric small GTPases and heterotrimeric complexes consisting of α, β, and γ subunits. G-protein coupled receptors (GPCRs) have seven transmembrane domains and interact with G-proteins via intracellular loops to transmit extracellular signals within the cell. Genetic variations in GPCRs can affect receptor functions like ligand binding and G-protein coupling, potentially causing diseases. Many single nucleotide polymorphisms and mutations have been linked to impaired or enhanced receptor signaling and diseases ranging from bleeding disorders to asthma, obesity, and immune deficiencies.
1. The study examines the role of C3G (RapGEF1) in skeletal muscle differentiation using C2C12 mouse myoblast cells.
2. The results show that C3G expression and protein levels increase as C2C12 cells differentiate into myotubes. Overexpression of C3G promotes myotube formation and muscle-specific marker expression.
3. Knockdown of C3G using shRNA impairs differentiation and increases cell death, indicating C3G is required for differentiation and cell survival in C2C12 cells. C3G regulates pathways involved in differentiation, proliferation, and cytoskeletal remodeling.
Characterising the Interactome of EZH2 in Embryonic Stem Cells (3)Daire Murphy
This study aimed to characterize the interactome of Ezh2, the core catalytic subunit of the PRC2 complex, in embryonic stem cells using mass spectrometry. Ezh2 and PRC2 are important for maintaining pluripotency and regulating stem cell differentiation through epigenetic modifications. The experimental interactome was enriched for chromatin remodeling proteins and transcriptional regulators as expected, as well as splicing factors, which prompted further analysis. Characterizing the interaction between splicing factors and PRC2 could provide insight into how stem cell differentiation is controlled while maintaining stemness, and how aberrations can cause cancer. Mass spectrometry identified potential high-confidence Ezh2 interactors and bioinformatics analysis revealed the complexity of the Ezh2 interactome
Genetic variations in G protein-coupled receptors (GPCRs) can alter receptor function and cause diseases. Single nucleotide polymorphisms and other mutations have been linked to impaired or enhanced receptor signaling. For example, a mutation in the vasopressin V2 receptor causes nephrogenic diabetes insipidus by decreasing ligand binding and receptor expression. Similarly, mutations in chemokine receptors CCR5 and CCR2 impact HIV infection by altering receptor function or interaction with other coreceptors. Overall, GPCR polymorphisms are associated with diseases by changing ligand binding, receptor activation, trafficking, and coupling to downstream signaling pathways.
This document summarizes a study examining how transforming growth factor beta (TGFβ) regulates expression of cysteine-rich protein 2 (CRP2) in vascular smooth muscle cells (VSMCs). The researchers found that TGFβ significantly induced CRP2 mRNA and protein expression in VSMCs. Promoter analysis identified a conserved cAMP-responsive element (CRE)-like site in the CRP2 promoter that was critical for basal promoter activity and response to TGFβ. Gel shift assays revealed that activating transcription factor 2 (ATF2) bound to this CRE-like element. TGFβ enhanced ATF2 phosphorylation and activation, leading to increased phospho-ATF2 levels and CRP2 promoter
This study investigated the role of histone H3 lysine 18 acetylation (H3K18ac) in maintaining pluripotency in embryonic stem cells. The researchers found that H3K18ac is highly enriched at stem cell genes in embryonic stem cells and levels decrease with differentiation. Expression of the E1A oncoprotein in mouse embryonic stem cells globally reduced H3K18ac and caused the cells to lose pluripotent characteristics, fail to activate stem cell enhancers, and suppress lineage-specific genes. Loss of pluripotency upon E1A expression required binding of E1A to the H3K18 acetyltransferases p300/CBP. This suggests H3K
MDM2 promotes the ubiquitination and degradation of FOXO transcription factors. The study found that MDM2 binds directly to FOXO1 and FOXO3A, promoting their ubiquitination and proteasome-mediated degradation. This degradation was dependent on FOXO phosphorylation by AKT and the E3 ligase activity of MDM2. Furthermore, activation of p53 led to increased MDM2 levels and degradation of endogenous FOXO3A. Therefore, MDM2 acts as an E3 ubiquitin ligase downstream of p53 to regulate FOXO protein stability.
1) The study investigates the role of b-catenin in myogenesis using P19 cells with reduced b-catenin activity (P19[shb-cat] cells) compared to control cells.
2) The loss of b-catenin resulted in reduced expression of genes involved in premyogenic mesoderm formation and skeletal myogenesis.
3) While retinoic acid could partially compensate by upregulating some precursor genes in P19[shb-cat] cells, it could not compensate for the expression of genes required for terminal myogenesis or overall skeletal muscle formation.
G-proteins are molecular switches that regulate various cellular activities. They exist in two classes: monomeric small GTPases and heterotrimeric complexes consisting of α, β, and γ subunits. G-protein coupled receptors (GPCRs) have seven transmembrane domains and interact with G-proteins via intracellular loops to transmit extracellular signals within the cell. Genetic variations in GPCRs can affect receptor functions like ligand binding and G-protein coupling, potentially causing diseases. Many single nucleotide polymorphisms and mutations have been linked to impaired or enhanced receptor signaling and diseases ranging from bleeding disorders to asthma, obesity, and immune deficiencies.
1. The study examines the role of C3G (RapGEF1) in skeletal muscle differentiation using C2C12 mouse myoblast cells.
2. The results show that C3G expression and protein levels increase as C2C12 cells differentiate into myotubes. Overexpression of C3G promotes myotube formation and muscle-specific marker expression.
3. Knockdown of C3G using shRNA impairs differentiation and increases cell death, indicating C3G is required for differentiation and cell survival in C2C12 cells. C3G regulates pathways involved in differentiation, proliferation, and cytoskeletal remodeling.
Characterising the Interactome of EZH2 in Embryonic Stem Cells (3)Daire Murphy
This study aimed to characterize the interactome of Ezh2, the core catalytic subunit of the PRC2 complex, in embryonic stem cells using mass spectrometry. Ezh2 and PRC2 are important for maintaining pluripotency and regulating stem cell differentiation through epigenetic modifications. The experimental interactome was enriched for chromatin remodeling proteins and transcriptional regulators as expected, as well as splicing factors, which prompted further analysis. Characterizing the interaction between splicing factors and PRC2 could provide insight into how stem cell differentiation is controlled while maintaining stemness, and how aberrations can cause cancer. Mass spectrometry identified potential high-confidence Ezh2 interactors and bioinformatics analysis revealed the complexity of the Ezh2 interactome
1) p53 activation through nutlin-3a treatment suppressed M2 macrophage polarization by downregulating M2 marker genes like c-MYC, IRF4 and FIZZ1.
2) Loss of p53 increased M2 macrophage polarization both in vitro and in vivo by increasing the expression of M2 marker genes.
3) p53 was found to suppress M2 macrophage polarization by directly binding to the promoter region of c-MYC gene, reducing its expression and influencing the expression of downstream M2 genes.
5-1. Review of complement system. Khadizha Emirova (eng)KidneyOrgRu
The document provides an overview of the complement system. It discusses that the complement system is composed of blood proteins that interact with each other and other immune system proteins to provide antimicrobial protection. It is activated via an enzymatic cascade reaction and its proteins only become active under pathological conditions. There are three pathways of complement activation: the classical, lectin, and alternative pathways. Complement activation leads to opsonization, inflammation, chemotaxis, and membrane attack complex formation. Tight regulation is needed as too much or too little complement can be harmful. Deficiencies in complement regulators can lead to innate autoreactivity.
Abstract
Mitogen-Activated Protein Kinase (MAPK) pathway is a signal transduction pathway that functions in a wide range of physiological and pathophysiological cellular events including cell proliferation, differentiation, apoptosis, migration, inflammation, metabolic disorders and diseases. In skeletal muscle, it plays an essential role in muscle fiber specialization, muscle mass maintenance, damage induced muscle regeneration and muscle diseases. This review provides an overview of MAPK pathway and its pathophysiological role in skeletal muscle diseases with a primary focus on muscular dystrophy and atrophy.
This document describes the development of a bimolecular fluorescence complementation (BiFC) assay to visualize and quantify interactions between the tumor suppressor protein p53 and its inhibitor Mdm2 in live mammalian cells. The assay uses fusion proteins containing non-fluorescent fragments of the Venus fluorescent protein tagged to p53 and Mdm2. Interaction between the proteins reconstitutes Venus fluorescence. Nutlin-3, a known disruptor of p53-Mdm2 binding, reduced BiFC signal and increased cell death when added, validating the assay. A library of 33 phosphatase inhibitors was also screened using this assay to identify potential modulators of p53-Mdm2 complex formation.
1. Receptor tyrosine kinases (RTKs) drive key cancer pathways and can be exploited as therapeutic targets, as shown by drugs like imatinib that inhibit mutated kinases in cancers.
2. RTK inhibitors have shown efficacy against cancers dependent on single kinases, but resistance often emerges through secondary mutations or bypass pathways.
3. Effective combination therapies are needed to overcome resistance, such as combining RTK inhibitors with other drugs that block downstream or bypass pathways.
Mesenchymal stem cells (MSCs) show promise for treating immune disorders and degenerative diseases. However, targeting MSCs to damaged tissue sites is challenging. The researchers hypothesized that engineering MSCs to express leukocyte adhesion molecules could enhance their homing ability. They coupled a recombinant form of P-selectin glycoprotein ligand-1 (PSGL-1), which mediates leukocyte rolling, to MSCs. This non-covalently coupled the PSGL-1 to the MSC surface. MSCs modified with PSGL-1 were then able to tether and roll on endothelial cells under flow, mimicking leukocyte behavior, suggesting this approach may help target MSCs to sites of injury and inflammation.
Stress granules (SGs) are cytoplasmic aggregates that form in response to cellular stress and contain translationally stalled messenger ribonucleoproteins (mRNPs). This study shows that neddylation, the covalent attachment of the ubiquitin-like protein NEDD8 to lysine residues on target proteins, promotes SG assembly in response to oxidative stress. Knockdown or inhibition of components of the neddylation pathway impairs stress-induced polysome disassembly and SG assembly. Proteomic analysis identified ribosomal proteins, translation factors, and RNA-binding proteins as potential targets of neddylation in translationally stalled fractions, including the RNA-binding protein SRSF3. SRSF3 is selectively
MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. MuSK binds BMP4, BMP2, and BMP7 with high nanomolar affinity through its Ig3 domain. In myoblasts, MuSK promotes BMP4-induced SMAD phosphorylation and Id1 expression. MuSK is required for the BMP4-induced expression of genes like Rgs4 that regulate calcium signaling. In myotubes, MuSK enhances the expression of genes characteristic of slow muscle in response to BMP4. MuSK acts as both a synaptic organizer through its kinase activity and as a BMP co-receptor modulating gene expression and signaling in muscle cells.
This study investigated the effects of limiting levels of the metabolite S-adenosylmethionine (SAM) on cell cycle progression. The researchers found that depleting SAM levels through methionine depletion or inhibition of methionine adenosyltransferase caused cells to arrest primarily in the G1 phase of the cell cycle. This G1 arrest was associated with activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Surprisingly, activity of the cyclin-dependent kinase Cdk4 remained high during the G1 arrest induced by SAM depletion, while activity of Cdk2 decreased along with cyclin E levels. The results demonstrate a new cell cycle checkpoint in response to
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
This study aims to analyze the distribution of 5-hydroxymethylcytosine (5-hmC) in the hippocampus of an Alzheimer's mouse model compared to healthy mice. DNA will be isolated from the hippocampus and analyzed using a microarray containing over 20,000 promoters and 15,000 CpG islands. Antibodies specific to 5-methylcytosine and 5-hmC will isolate DNA fragments containing these modifications, which will then be amplified and compared between the transgenic and healthy mice to assess epigenetic changes associated with Alzheimer's Disease. The results are expected to show increases, decreases, or no change in 5-hmC levels in the transgenic mouse model compared to controls.
The complement system is an important part of the innate immune system that promotes clearance of foreign particles and initiation of adaptive immune responses. It involves around 30 cell-associated and fluid phase proteins that are activated in a cascade of enzyme reactions. There are three pathways of complement activation - the classical, lectin, and alternative pathways. Complement activity is tightly regulated to protect host cells, and regulation occurs through mechanisms such as component instability, differences in cell surface carbohydrates between microbes and host cells, and regulatory proteins that inhibit or destroy complement components.
Blain_AlzResTherapy_2016_Characterization of FRM-36143 as a new γ-secretase m...Gerhard Koenig
FRM-36143 is a novel γ-secretase modulator (GSM) that was characterized for its potential to treat familial Alzheimer's disease (FAD). In vitro assays showed that FRM-36143 has improved central nervous system drug properties compared to other published GSMs, with an EC50 of 35 nM for reducing Aβ42 production. It increased production of non-toxic Aβ peptides and reversed the effects of presenilin mutations on amyloid beta processing without inhibiting Notch processing or other off-target effects. In vivo studies in mice and rats showed FRM-36143 reduced Aβ42 levels in cerebrospinal fluid. Due to its ability to reverse presenilin mutations
CETP overexpression in diabetic and obese db/db mice prevented the formation of diet-induced atherosclerotic plaques in the aorta. Mice overexpressing CETP had lower total cholesterol concentrations and less cholesterol in the VLDL and IDL/LDL subfractions compared to db/db mice. This study suggests CETP plays an anti-atherogenic role in the context of diabetic obesity by lowering atherogenic lipids and preventing plaque formation.
Epidermal growth factor and its receptor tyrosine kinaseGedion Yilma
The document discusses epidermal growth factor (EGF) signaling and the EGF receptor. It notes that EGF is involved in normal cell processes like development, differentiation, and wound healing. The EGF receptor belongs to the ErbB family of receptor tyrosine kinases and plays a key role in signaling pathways regulating cell proliferation, survival, and apoptosis. Overexpression or abnormal activation of the EGF receptor and other ErbB family members is implicated in many epithelial cancers.
The document discusses several studies related to atherosclerosis and cardiovascular disease:
1) A study finds that a polymorphism in the Fas gene promoter region is a genetic risk factor for myocardial infarction by modulating Fas expression.
2) Immunoglobulin treatment suppresses atherosclerosis in mice via its Fc portion by reducing macrophage accumulation in lesions.
3) Inhibition of NF-kB reduces inflammatory molecule expression and attenuates atherosclerosis in mice.
4) MMP-8 may represent a new collagenolytic pathway in acute plaque disruption based on its levels in carotid plaques from patients.
This document discusses drug transporter polymorphism and its effects. It begins by introducing drug transporter proteins and how genetic variations can affect drug uptake, distribution, and toxicity. It then examines these effects for the cancer drug irinotecan in particular. The rest of the document details the two main classes of drug transporter proteins - ATP-binding cassette (ABC) transporters and solute carrier (SLC) proteins. It provides examples of specific transporters like P-glycoprotein, MRP1, BCRP, and discusses their tissue expression and drug substrates. In closing, it lists several important transporter genes and the substrates they transport.
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
1) The document discusses glycogen synthase kinase-3 (GSK-3) and how its activity is inhibited by lithium, which may contribute to lithium's neuroprotective effects. GSK-3 phosphorylates proteins involved in key signaling pathways like Wnt and insulin.
2) Lithium inhibits GSK-3 through direct binding as well as activating the PI3K/Akt pathway, which phosphorylates and inhibits GSK-3. This allows proteins like beta-catenin to avoid degradation and influence pro-survival gene transcription.
3) By inhibiting GSK-3, lithium can protect neurons from various insults like trophic factor withdrawal, toxins, and ischemia/oxid
C3G overexpression induces long, actin-rich neurite-like extensions in aggressive breast cancer cell lines MDA-MB-231 and BT549, but not in other cancer cell lines tested. These extensions resemble neuronal processes and contain nodes, branches, and microspikes. C3G expression is associated with stabilization of microtubules and reduced motility of MDA-MB-231 cells compared to control cells. Both the catalytic and protein interaction domains of C3G contribute to its ability to induce these neurite-like extensions.
Effect of DX and Phosphorylation of Gal3-Binding Partner Interactions Draft 08Matthew Rotondi
This document summarizes research examining how covalent modification and phosphorylation of galectin-3 affects its binding to various protein partners. The researchers found that modification of galectin-3 by DX-52-1, a cell-permanent inhibitor, reduced binding to some proteins but not others. Phosphorylation of galectin-3 at two sites also reduced binding to all proteins tested. DX-52-1 further decreased binding of modified galectin-3 to two proteins. The results suggest galectin-3 interacts differently with binding partners and that modification and phosphorylation impact these interactions in partner-specific ways.
1) p53 activation through nutlin-3a treatment suppressed M2 macrophage polarization by downregulating M2 marker genes like c-MYC, IRF4 and FIZZ1.
2) Loss of p53 increased M2 macrophage polarization both in vitro and in vivo by increasing the expression of M2 marker genes.
3) p53 was found to suppress M2 macrophage polarization by directly binding to the promoter region of c-MYC gene, reducing its expression and influencing the expression of downstream M2 genes.
5-1. Review of complement system. Khadizha Emirova (eng)KidneyOrgRu
The document provides an overview of the complement system. It discusses that the complement system is composed of blood proteins that interact with each other and other immune system proteins to provide antimicrobial protection. It is activated via an enzymatic cascade reaction and its proteins only become active under pathological conditions. There are three pathways of complement activation: the classical, lectin, and alternative pathways. Complement activation leads to opsonization, inflammation, chemotaxis, and membrane attack complex formation. Tight regulation is needed as too much or too little complement can be harmful. Deficiencies in complement regulators can lead to innate autoreactivity.
Abstract
Mitogen-Activated Protein Kinase (MAPK) pathway is a signal transduction pathway that functions in a wide range of physiological and pathophysiological cellular events including cell proliferation, differentiation, apoptosis, migration, inflammation, metabolic disorders and diseases. In skeletal muscle, it plays an essential role in muscle fiber specialization, muscle mass maintenance, damage induced muscle regeneration and muscle diseases. This review provides an overview of MAPK pathway and its pathophysiological role in skeletal muscle diseases with a primary focus on muscular dystrophy and atrophy.
This document describes the development of a bimolecular fluorescence complementation (BiFC) assay to visualize and quantify interactions between the tumor suppressor protein p53 and its inhibitor Mdm2 in live mammalian cells. The assay uses fusion proteins containing non-fluorescent fragments of the Venus fluorescent protein tagged to p53 and Mdm2. Interaction between the proteins reconstitutes Venus fluorescence. Nutlin-3, a known disruptor of p53-Mdm2 binding, reduced BiFC signal and increased cell death when added, validating the assay. A library of 33 phosphatase inhibitors was also screened using this assay to identify potential modulators of p53-Mdm2 complex formation.
1. Receptor tyrosine kinases (RTKs) drive key cancer pathways and can be exploited as therapeutic targets, as shown by drugs like imatinib that inhibit mutated kinases in cancers.
2. RTK inhibitors have shown efficacy against cancers dependent on single kinases, but resistance often emerges through secondary mutations or bypass pathways.
3. Effective combination therapies are needed to overcome resistance, such as combining RTK inhibitors with other drugs that block downstream or bypass pathways.
Mesenchymal stem cells (MSCs) show promise for treating immune disorders and degenerative diseases. However, targeting MSCs to damaged tissue sites is challenging. The researchers hypothesized that engineering MSCs to express leukocyte adhesion molecules could enhance their homing ability. They coupled a recombinant form of P-selectin glycoprotein ligand-1 (PSGL-1), which mediates leukocyte rolling, to MSCs. This non-covalently coupled the PSGL-1 to the MSC surface. MSCs modified with PSGL-1 were then able to tether and roll on endothelial cells under flow, mimicking leukocyte behavior, suggesting this approach may help target MSCs to sites of injury and inflammation.
Stress granules (SGs) are cytoplasmic aggregates that form in response to cellular stress and contain translationally stalled messenger ribonucleoproteins (mRNPs). This study shows that neddylation, the covalent attachment of the ubiquitin-like protein NEDD8 to lysine residues on target proteins, promotes SG assembly in response to oxidative stress. Knockdown or inhibition of components of the neddylation pathway impairs stress-induced polysome disassembly and SG assembly. Proteomic analysis identified ribosomal proteins, translation factors, and RNA-binding proteins as potential targets of neddylation in translationally stalled fractions, including the RNA-binding protein SRSF3. SRSF3 is selectively
MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. MuSK binds BMP4, BMP2, and BMP7 with high nanomolar affinity through its Ig3 domain. In myoblasts, MuSK promotes BMP4-induced SMAD phosphorylation and Id1 expression. MuSK is required for the BMP4-induced expression of genes like Rgs4 that regulate calcium signaling. In myotubes, MuSK enhances the expression of genes characteristic of slow muscle in response to BMP4. MuSK acts as both a synaptic organizer through its kinase activity and as a BMP co-receptor modulating gene expression and signaling in muscle cells.
This study investigated the effects of limiting levels of the metabolite S-adenosylmethionine (SAM) on cell cycle progression. The researchers found that depleting SAM levels through methionine depletion or inhibition of methionine adenosyltransferase caused cells to arrest primarily in the G1 phase of the cell cycle. This G1 arrest was associated with activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Surprisingly, activity of the cyclin-dependent kinase Cdk4 remained high during the G1 arrest induced by SAM depletion, while activity of Cdk2 decreased along with cyclin E levels. The results demonstrate a new cell cycle checkpoint in response to
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
This study aims to analyze the distribution of 5-hydroxymethylcytosine (5-hmC) in the hippocampus of an Alzheimer's mouse model compared to healthy mice. DNA will be isolated from the hippocampus and analyzed using a microarray containing over 20,000 promoters and 15,000 CpG islands. Antibodies specific to 5-methylcytosine and 5-hmC will isolate DNA fragments containing these modifications, which will then be amplified and compared between the transgenic and healthy mice to assess epigenetic changes associated with Alzheimer's Disease. The results are expected to show increases, decreases, or no change in 5-hmC levels in the transgenic mouse model compared to controls.
The complement system is an important part of the innate immune system that promotes clearance of foreign particles and initiation of adaptive immune responses. It involves around 30 cell-associated and fluid phase proteins that are activated in a cascade of enzyme reactions. There are three pathways of complement activation - the classical, lectin, and alternative pathways. Complement activity is tightly regulated to protect host cells, and regulation occurs through mechanisms such as component instability, differences in cell surface carbohydrates between microbes and host cells, and regulatory proteins that inhibit or destroy complement components.
Blain_AlzResTherapy_2016_Characterization of FRM-36143 as a new γ-secretase m...Gerhard Koenig
FRM-36143 is a novel γ-secretase modulator (GSM) that was characterized for its potential to treat familial Alzheimer's disease (FAD). In vitro assays showed that FRM-36143 has improved central nervous system drug properties compared to other published GSMs, with an EC50 of 35 nM for reducing Aβ42 production. It increased production of non-toxic Aβ peptides and reversed the effects of presenilin mutations on amyloid beta processing without inhibiting Notch processing or other off-target effects. In vivo studies in mice and rats showed FRM-36143 reduced Aβ42 levels in cerebrospinal fluid. Due to its ability to reverse presenilin mutations
CETP overexpression in diabetic and obese db/db mice prevented the formation of diet-induced atherosclerotic plaques in the aorta. Mice overexpressing CETP had lower total cholesterol concentrations and less cholesterol in the VLDL and IDL/LDL subfractions compared to db/db mice. This study suggests CETP plays an anti-atherogenic role in the context of diabetic obesity by lowering atherogenic lipids and preventing plaque formation.
Epidermal growth factor and its receptor tyrosine kinaseGedion Yilma
The document discusses epidermal growth factor (EGF) signaling and the EGF receptor. It notes that EGF is involved in normal cell processes like development, differentiation, and wound healing. The EGF receptor belongs to the ErbB family of receptor tyrosine kinases and plays a key role in signaling pathways regulating cell proliferation, survival, and apoptosis. Overexpression or abnormal activation of the EGF receptor and other ErbB family members is implicated in many epithelial cancers.
The document discusses several studies related to atherosclerosis and cardiovascular disease:
1) A study finds that a polymorphism in the Fas gene promoter region is a genetic risk factor for myocardial infarction by modulating Fas expression.
2) Immunoglobulin treatment suppresses atherosclerosis in mice via its Fc portion by reducing macrophage accumulation in lesions.
3) Inhibition of NF-kB reduces inflammatory molecule expression and attenuates atherosclerosis in mice.
4) MMP-8 may represent a new collagenolytic pathway in acute plaque disruption based on its levels in carotid plaques from patients.
This document discusses drug transporter polymorphism and its effects. It begins by introducing drug transporter proteins and how genetic variations can affect drug uptake, distribution, and toxicity. It then examines these effects for the cancer drug irinotecan in particular. The rest of the document details the two main classes of drug transporter proteins - ATP-binding cassette (ABC) transporters and solute carrier (SLC) proteins. It provides examples of specific transporters like P-glycoprotein, MRP1, BCRP, and discusses their tissue expression and drug substrates. In closing, it lists several important transporter genes and the substrates they transport.
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
1) The document discusses glycogen synthase kinase-3 (GSK-3) and how its activity is inhibited by lithium, which may contribute to lithium's neuroprotective effects. GSK-3 phosphorylates proteins involved in key signaling pathways like Wnt and insulin.
2) Lithium inhibits GSK-3 through direct binding as well as activating the PI3K/Akt pathway, which phosphorylates and inhibits GSK-3. This allows proteins like beta-catenin to avoid degradation and influence pro-survival gene transcription.
3) By inhibiting GSK-3, lithium can protect neurons from various insults like trophic factor withdrawal, toxins, and ischemia/oxid
C3G overexpression induces long, actin-rich neurite-like extensions in aggressive breast cancer cell lines MDA-MB-231 and BT549, but not in other cancer cell lines tested. These extensions resemble neuronal processes and contain nodes, branches, and microspikes. C3G expression is associated with stabilization of microtubules and reduced motility of MDA-MB-231 cells compared to control cells. Both the catalytic and protein interaction domains of C3G contribute to its ability to induce these neurite-like extensions.
Effect of DX and Phosphorylation of Gal3-Binding Partner Interactions Draft 08Matthew Rotondi
This document summarizes research examining how covalent modification and phosphorylation of galectin-3 affects its binding to various protein partners. The researchers found that modification of galectin-3 by DX-52-1, a cell-permanent inhibitor, reduced binding to some proteins but not others. Phosphorylation of galectin-3 at two sites also reduced binding to all proteins tested. DX-52-1 further decreased binding of modified galectin-3 to two proteins. The results suggest galectin-3 interacts differently with binding partners and that modification and phosphorylation impact these interactions in partner-specific ways.
This document discusses targeting tau protein with GSK-3β inhibitors such as Tideglusib in the treatment of Alzheimer's disease. It provides background on tau protein and its role in neurofibrillary tangles. GSK-3β is an enzyme involved in tau hyperphosphorylation, and inhibitors such as the non-ATP competitive inhibitor Tideglusib have shown promise in reducing tau pathology in animal models. Clinical trials of Tideglusib in Alzheimer's patients showed it was well tolerated but did not meet efficacy endpoints. Further research into GSK-3β inhibitors is still warranted given tau's role in the disease.
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNT) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
Cell signalling and signal transduction Communication between cells from karpNusrat Gulbarga
Virtually every activity in which a cell is engaged is regulated by signals originating at the cell surface. This overall process in which information carried by extracellular messenger molecules is translated into changes that occur in- side a cell is referred to as signal transduction.
This document discusses the identification of Necdin as a novel STAT3 target gene that is downregulated in human cancer. The researchers used microarray analysis to compare gene expression profiles between cells with constitutively active STAT3 and normal cells. They identified differentially expressed genes between cells expressing oncogenic v-Src or constitutively active STAT3-C. Genes common to both lists were most likely directly regulated by STAT3. Computational analysis identified Necdin, a negative growth regulator, as downregulated in cells with active STAT3. Experiments confirmed STAT3 directly binds to and regulates the Necdin promoter, and Necdin expression inversely correlates with STAT3 activity in cancer cell lines. This suggests STAT
p53 Protein: Master Regulator of Apoptosis and its Application in Cancer TherapyBRNSS Publication Hub
Cancer is characterized by uncontrolled and abnormal cells growth. In the body, the cell growth and cell
division are governing by apoptosis. The process of apoptosis is mainly regulated by the p53 protein. p53
is a tumor suppressor protein. The amount of p53 in a cell is mainly controlled by the negative regulator
murine double minute 2 (MDM2), which on complex formation with p53 leads to an overall reduction
of the p53 level. Inhibition of p53 function will inhibit the apoptosis and leads to cancer. Consequently,
inhibition of the MDM2/p53 interaction using the small molecules activates the p53 function and apoptosis
in the cells which contain the wild-type p53. It is a promising new therapeutic strategy for the treatment
of cancers retaining wild-type p53. However, the safety window of this class of compounds must be
evaluated. Moreover, it has to require the development of compounds, which can also be able to target the
cells which contain the mutated or deleted p53.
C3G interacts with and inhibits the function of β-catenin. C3G forms a complex with β-catenin through its central proline-rich domain. Overexpression of C3G inhibits β-catenin/TCF transcriptional activity and destabilizes β-catenin protein levels by promoting its degradation. β-catenin activation leads to reduced expression of C3G, indicating reciprocal negative regulation between C3G and β-catenin. C3G exerts these effects on β-catenin independently of its guanine nucleotide exchange factor activity or GSK3β phosphorylation of β-catenin.
The document summarizes the structure and function of the p53 tumor suppressor protein. It describes the various domains of p53 including the N-terminal domain, proline-rich domain, central DNA-binding domain, tetramerization domain, and C-terminal regulatory domain. It discusses how each domain contributes to p53's role in regulating genes involved in cell cycle arrest and apoptosis in response to cellular stress. The document also provides information on the location of the TP53 gene and includes figures depicting the structure and domains of the p53 protein.
This document summarizes two important tumor suppressor genes - PRB and P53. It provides background on tumor suppressor genes, noting that they function through loss of function to regulate cell cycle and suppress uncontrolled cell proliferation. For PRB, it describes its role in retinoblastoma cancer and cell cycle regulation. For P53, it discusses its role as the "guardian of the genome" in DNA repair and apoptosis, as well as its structure and functions in halting the cell cycle when damage is detected.
1) The study found that inhibiting HDAC3 with the selective inhibitor MI192 increased tubulin acetylation levels and disrupted microtubule dynamics in prostate cancer cells.
2) Knockdown of HDAC3 using siRNA also increased tubulin acetylation levels, while overexpression of HDAC3 reduced acetylation.
3) However, in vitro assays showed that the HDAC3-SMRT-DAD complex did not directly deacetylate tubulin, suggesting HDAC3 modulates tubulin acetylation indirectly.
C3G is a guanine nucleotide exchange factor that activates small GTPases involved in cytoskeletal remodeling and cellular signaling pathways. It plays an important role in mammalian embryonic development and regulates processes like adhesion, migration, differentiation and apoptosis. C3G signals through the activation of Ras family GTPases like Rap1 and Rho family member TC10 to modulate downstream effectors such as MAPK and Rac, influencing the actin cytoskeleton. Deregulation of C3G signaling has been implicated in various disorders and it may be a potential therapeutic target.
STAT3, a member of the STAT family, is a latent transcription factor that is activated in response to various cytokines, growth factors, and oncogene signals. STAT3 is constitutively activated in various human cancers, and its activation is frequently associated with poor prognosis. As a transcription factor, STAT3 regulates a set of genes implicated in cancer cell survival, proliferation, angiogenesis, invasion, metastasis, drug resistance, and immune evasion. Medicilon provides STAT3 drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services.
https://www.medicilon.com/platform/stat3-targeted-drugs/
This document discusses the role of STAT3 in skin disorders like psoriasis. It begins by providing background on the STAT family of proteins and how they function as signal transducers and transcription factors in response to extracellular ligands. It then focuses on STAT3 specifically, describing how it is activated by cytokines and other signaling molecules. The document discusses STAT3's role in keratinocyte migration and signaling pathways relevant to psoriasis pathogenesis. It notes that STAT3 links activated keratinocytes and immune cells required for psoriasis development.
This document summarizes recent research on the role of epigenetic regulation in human cancers. It discusses how epigenetic mechanisms like DNA methylation and histone modifications can disrupt gene expression and lead to tumorigenesis. Specifically, it describes how hypermethylation of CpG islands can silence tumor suppressor genes, and how certain histone modifications are associated with transcriptional activation or repression. The document also reviews emerging epigenetic therapies and challenges in the field, such as a lack of predictive biomarkers and unclear mechanisms of response/resistance.
The Notch signaling pathway regulates cell proliferation, stem cell maintenance, differentiation, and homeostasis. Mammals have four Notch receptors that are single-pass transmembrane proteins composed of extracellular and intracellular portions. Notch signaling is initiated by ligand binding and proteolytic cleavage of the receptor. The cleaved intracellular domain then translocates to the nucleus to regulate transcription of target genes. Crosstalk between signaling pathways like Notch and YAP/TAZ can impact processes like stem cell self-renewal and differentiation. Notch signaling can be inhibited by blocking receptor cleavage with γ-secretase inhibitors or interfering with ligand-receptor interaction using monoclonal antibodies.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
1) GRK5 regulates prostate cancer cell migration and invasion in vitro and tumor growth and metastasis in vivo.
2) GRK5 phosphorylates the cytoskeletal protein moesin, regulating its subcellular distribution and localization to the cell periphery.
3) Phosphorylation of moesin at threonine 66 by GRK5 is important for cell spreading, and mutation of this site reduces cell spreading.
AI 101: An Introduction to the Basics and Impact of Artificial IntelligenceIndexBug
Imagine a world where machines not only perform tasks but also learn, adapt, and make decisions. This is the promise of Artificial Intelligence (AI), a technology that's not just enhancing our lives but revolutionizing entire industries.
Introduction of Cybersecurity with OSS at Code Europe 2024Hiroshi SHIBATA
I develop the Ruby programming language, RubyGems, and Bundler, which are package managers for Ruby. Today, I will introduce how to enhance the security of your application using open-source software (OSS) examples from Ruby and RubyGems.
The first topic is CVE (Common Vulnerabilities and Exposures). I have published CVEs many times. But what exactly is a CVE? I'll provide a basic understanding of CVEs and explain how to detect and handle vulnerabilities in OSS.
Next, let's discuss package managers. Package managers play a critical role in the OSS ecosystem. I'll explain how to manage library dependencies in your application.
I'll share insights into how the Ruby and RubyGems core team works to keep our ecosystem safe. By the end of this talk, you'll have a better understanding of how to safeguard your code.
Cosa hanno in comune un mattoncino Lego e la backdoor XZ?Speck&Tech
ABSTRACT: A prima vista, un mattoncino Lego e la backdoor XZ potrebbero avere in comune il fatto di essere entrambi blocchi di costruzione, o dipendenze di progetti creativi e software. La realtà è che un mattoncino Lego e il caso della backdoor XZ hanno molto di più di tutto ciò in comune.
Partecipate alla presentazione per immergervi in una storia di interoperabilità, standard e formati aperti, per poi discutere del ruolo importante che i contributori hanno in una comunità open source sostenibile.
BIO: Sostenitrice del software libero e dei formati standard e aperti. È stata un membro attivo dei progetti Fedora e openSUSE e ha co-fondato l'Associazione LibreItalia dove è stata coinvolta in diversi eventi, migrazioni e formazione relativi a LibreOffice. In precedenza ha lavorato a migrazioni e corsi di formazione su LibreOffice per diverse amministrazioni pubbliche e privati. Da gennaio 2020 lavora in SUSE come Software Release Engineer per Uyuni e SUSE Manager e quando non segue la sua passione per i computer e per Geeko coltiva la sua curiosità per l'astronomia (da cui deriva il suo nickname deneb_alpha).
Threats to mobile devices are more prevalent and increasing in scope and complexity. Users of mobile devices desire to take full advantage of the features
available on those devices, but many of the features provide convenience and capability but sacrifice security. This best practices guide outlines steps the users can take to better protect personal devices and information.
Salesforce Integration for Bonterra Impact Management (fka Social Solutions A...Jeffrey Haguewood
Sidekick Solutions uses Bonterra Impact Management (fka Social Solutions Apricot) and automation solutions to integrate data for business workflows.
We believe integration and automation are essential to user experience and the promise of efficient work through technology. Automation is the critical ingredient to realizing that full vision. We develop integration products and services for Bonterra Case Management software to support the deployment of automations for a variety of use cases.
This video focuses on integration of Salesforce with Bonterra Impact Management.
Interested in deploying an integration with Salesforce for Bonterra Impact Management? Contact us at sales@sidekicksolutionsllc.com to discuss next steps.
Fueling AI with Great Data with Airbyte WebinarZilliz
This talk will focus on how to collect data from a variety of sources, leveraging this data for RAG and other GenAI use cases, and finally charting your course to productionalization.
Best 20 SEO Techniques To Improve Website Visibility In SERPPixlogix Infotech
Boost your website's visibility with proven SEO techniques! Our latest blog dives into essential strategies to enhance your online presence, increase traffic, and rank higher on search engines. From keyword optimization to quality content creation, learn how to make your site stand out in the crowded digital landscape. Discover actionable tips and expert insights to elevate your SEO game.
Monitoring and Managing Anomaly Detection on OpenShift.pdfTosin Akinosho
Monitoring and Managing Anomaly Detection on OpenShift
Overview
Dive into the world of anomaly detection on edge devices with our comprehensive hands-on tutorial. This SlideShare presentation will guide you through the entire process, from data collection and model training to edge deployment and real-time monitoring. Perfect for those looking to implement robust anomaly detection systems on resource-constrained IoT/edge devices.
Key Topics Covered
1. Introduction to Anomaly Detection
- Understand the fundamentals of anomaly detection and its importance in identifying unusual behavior or failures in systems.
2. Understanding Edge (IoT)
- Learn about edge computing and IoT, and how they enable real-time data processing and decision-making at the source.
3. What is ArgoCD?
- Discover ArgoCD, a declarative, GitOps continuous delivery tool for Kubernetes, and its role in deploying applications on edge devices.
4. Deployment Using ArgoCD for Edge Devices
- Step-by-step guide on deploying anomaly detection models on edge devices using ArgoCD.
5. Introduction to Apache Kafka and S3
- Explore Apache Kafka for real-time data streaming and Amazon S3 for scalable storage solutions.
6. Viewing Kafka Messages in the Data Lake
- Learn how to view and analyze Kafka messages stored in a data lake for better insights.
7. What is Prometheus?
- Get to know Prometheus, an open-source monitoring and alerting toolkit, and its application in monitoring edge devices.
8. Monitoring Application Metrics with Prometheus
- Detailed instructions on setting up Prometheus to monitor the performance and health of your anomaly detection system.
9. What is Camel K?
- Introduction to Camel K, a lightweight integration framework built on Apache Camel, designed for Kubernetes.
10. Configuring Camel K Integrations for Data Pipelines
- Learn how to configure Camel K for seamless data pipeline integrations in your anomaly detection workflow.
11. What is a Jupyter Notebook?
- Overview of Jupyter Notebooks, an open-source web application for creating and sharing documents with live code, equations, visualizations, and narrative text.
12. Jupyter Notebooks with Code Examples
- Hands-on examples and code snippets in Jupyter Notebooks to help you implement and test anomaly detection models.
5th LF Energy Power Grid Model Meet-up SlidesDanBrown980551
5th Power Grid Model Meet-up
It is with great pleasure that we extend to you an invitation to the 5th Power Grid Model Meet-up, scheduled for 6th June 2024. This event will adopt a hybrid format, allowing participants to join us either through an online Mircosoft Teams session or in person at TU/e located at Den Dolech 2, Eindhoven, Netherlands. The meet-up will be hosted by Eindhoven University of Technology (TU/e), a research university specializing in engineering science & technology.
Power Grid Model
The global energy transition is placing new and unprecedented demands on Distribution System Operators (DSOs). Alongside upgrades to grid capacity, processes such as digitization, capacity optimization, and congestion management are becoming vital for delivering reliable services.
Power Grid Model is an open source project from Linux Foundation Energy and provides a calculation engine that is increasingly essential for DSOs. It offers a standards-based foundation enabling real-time power systems analysis, simulations of electrical power grids, and sophisticated what-if analysis. In addition, it enables in-depth studies and analysis of the electrical power grid’s behavior and performance. This comprehensive model incorporates essential factors such as power generation capacity, electrical losses, voltage levels, power flows, and system stability.
Power Grid Model is currently being applied in a wide variety of use cases, including grid planning, expansion, reliability, and congestion studies. It can also help in analyzing the impact of renewable energy integration, assessing the effects of disturbances or faults, and developing strategies for grid control and optimization.
What to expect
For the upcoming meetup we are organizing, we have an exciting lineup of activities planned:
-Insightful presentations covering two practical applications of the Power Grid Model.
-An update on the latest advancements in Power Grid -Model technology during the first and second quarters of 2024.
-An interactive brainstorming session to discuss and propose new feature requests.
-An opportunity to connect with fellow Power Grid Model enthusiasts and users.
Main news related to the CCS TSI 2023 (2023/1695)Jakub Marek
An English 🇬🇧 translation of a presentation to the speech I gave about the main changes brought by CCS TSI 2023 at the biggest Czech conference on Communications and signalling systems on Railways, which was held in Clarion Hotel Olomouc from 7th to 9th November 2023 (konferenceszt.cz). Attended by around 500 participants and 200 on-line followers.
The original Czech 🇨🇿 version of the presentation can be found here: https://www.slideshare.net/slideshow/hlavni-novinky-souvisejici-s-ccs-tsi-2023-2023-1695/269688092 .
The videorecording (in Czech) from the presentation is available here: https://youtu.be/WzjJWm4IyPk?si=SImb06tuXGb30BEH .
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
Are you ready to revolutionize how you handle data? Join us for a webinar where we’ll bring you up to speed with the latest advancements in Generative AI technology and discover how leveraging FME with tools from giants like Google Gemini, Amazon, and Microsoft OpenAI can supercharge your workflow efficiency.
During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
Ollama Use Case: Learn how Scenario Specialist Dmitri Bagh has utilized Ollama within FME to input data, create custom models, and enhance security protocols. This segment will include demos to illustrate the full capabilities of FME in AI-driven processes.
Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
Generating privacy-protected synthetic data using Secludy and MilvusZilliz
During this demo, the founders of Secludy will demonstrate how their system utilizes Milvus to store and manipulate embeddings for generating privacy-protected synthetic data. Their approach not only maintains the confidentiality of the original data but also enhances the utility and scalability of LLMs under privacy constraints. Attendees, including machine learning engineers, data scientists, and data managers, will witness first-hand how Secludy's integration with Milvus empowers organizations to harness the power of LLMs securely and efficiently.
Programming Foundation Models with DSPy - Meetup SlidesZilliz
Prompting language models is hard, while programming language models is easy. In this talk, I will discuss the state-of-the-art framework DSPy for programming foundation models with its powerful optimizers and runtime constraint system.
HCL Notes und Domino Lizenzkostenreduzierung in der Welt von DLAUpanagenda
Webinar Recording: https://www.panagenda.com/webinars/hcl-notes-und-domino-lizenzkostenreduzierung-in-der-welt-von-dlau/
DLAU und die Lizenzen nach dem CCB- und CCX-Modell sind für viele in der HCL-Community seit letztem Jahr ein heißes Thema. Als Notes- oder Domino-Kunde haben Sie vielleicht mit unerwartet hohen Benutzerzahlen und Lizenzgebühren zu kämpfen. Sie fragen sich vielleicht, wie diese neue Art der Lizenzierung funktioniert und welchen Nutzen sie Ihnen bringt. Vor allem wollen Sie sicherlich Ihr Budget einhalten und Kosten sparen, wo immer möglich. Das verstehen wir und wir möchten Ihnen dabei helfen!
Wir erklären Ihnen, wie Sie häufige Konfigurationsprobleme lösen können, die dazu führen können, dass mehr Benutzer gezählt werden als nötig, und wie Sie überflüssige oder ungenutzte Konten identifizieren und entfernen können, um Geld zu sparen. Es gibt auch einige Ansätze, die zu unnötigen Ausgaben führen können, z. B. wenn ein Personendokument anstelle eines Mail-Ins für geteilte Mailboxen verwendet wird. Wir zeigen Ihnen solche Fälle und deren Lösungen. Und natürlich erklären wir Ihnen das neue Lizenzmodell.
Nehmen Sie an diesem Webinar teil, bei dem HCL-Ambassador Marc Thomas und Gastredner Franz Walder Ihnen diese neue Welt näherbringen. Es vermittelt Ihnen die Tools und das Know-how, um den Überblick zu bewahren. Sie werden in der Lage sein, Ihre Kosten durch eine optimierte Domino-Konfiguration zu reduzieren und auch in Zukunft gering zu halten.
Diese Themen werden behandelt
- Reduzierung der Lizenzkosten durch Auffinden und Beheben von Fehlkonfigurationen und überflüssigen Konten
- Wie funktionieren CCB- und CCX-Lizenzen wirklich?
- Verstehen des DLAU-Tools und wie man es am besten nutzt
- Tipps für häufige Problembereiche, wie z. B. Team-Postfächer, Funktions-/Testbenutzer usw.
- Praxisbeispiele und Best Practices zum sofortigen Umsetzen
Building Production Ready Search Pipelines with Spark and MilvusZilliz
Spark is the widely used ETL tool for processing, indexing and ingesting data to serving stack for search. Milvus is the production-ready open-source vector database. In this talk we will show how to use Spark to process unstructured data to extract vector representations, and push the vectors to Milvus vector database for search serving.
Have you ever been confused by the myriad of choices offered by AWS for hosting a website or an API?
Lambda, Elastic Beanstalk, Lightsail, Amplify, S3 (and more!) can each host websites + APIs. But which one should we choose?
Which one is cheapest? Which one is fastest? Which one will scale to meet our needs?
Join me in this session as we dive into each AWS hosting service to determine which one is best for your scenario and explain why!
Choosing The Best AWS Service For Your Website + API.pptx
930710.v2
1. GSK-3β: a bifunctional role in cell death pathways
Keith M Jacobs1, Sandeep R Bhave2, Daniel J Ferraro1, Jerry J Jaboin1, 4, Dennis E Hallahan1, 3 4 , Dinesh
Thotala1,4,*
1
Department of Radiation Oncology, Washington University, St. Louis, MO
2
, Vanderbilt University School of Medicine, Nashville, TN
3
Mallinckrodt Institute of Radiology, St. Louis, MO
4
Siteman Cancer Center, St. Louis, MO
Corresponding author: Dinesh Thotala, Ph.D., Department of Radiation Oncology, Washington University
in St. Louis, 4511 Forest Park, St. Louis, MO, 63108 Tel.: 314-747-5456, e-mail:
dthotala@radonc.wustl.edu.
2. ABSTRACT:
Although Glycogen synthase kinase-3 beta (GSK-3β) was originally named for its ability to phosphorylate
glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be
a key regulator of a wide range of cellular functions. GSK-3β is involved in modulating a variety of
functions including cell signaling, growth metabolism and various transcription factors that determines
the survival or death of the organism. Secondary to the role of GSK-3β in various diseases including
Alzheimer’s disease, inflammation, diabetes and cancer, small molecule inhibitors of GSK-3β are gaining
significant attention. This review is primarily focused on addressing the bifunctional or conflicting roles
of GSK-3β in both the promotion of cell survival and of apoptosis. GSK-3β has emerged as an important
molecular target for drug development.
3. INTRODUCTION:
Glycogen synthase kinase-3 is a ubiquitously expressed protein kinase that exists in two isoforms, α and
β. Originally identified based on its role in glycogen biosynthesis based on its inactivating
phosphorylation of glycogen synthase, it has since been found to regulate a myriad of functions through
Wnt and other signaling pathways[1]. The two isoforms are strongly conserved within their kinase
domain but differ greatly at the C-terminus, while the α isoform additionally contains a glycine-rich N-
terminus extension[2]. Our review will focus on the β isoform due to its more established role in cell
survival and viability. Glycogen synthase kinase-3 beta (GSK-3β) is involved in the regulation of a wide
range of cellular functions including differentiation, growth, proliferation, motility, cell cycle
progression, embryonic development, apoptosis, and insulin response [1-8]. It has emerged as an
important regulator of neuronal, endothelial, hepatocyte, fibroblast, and astrocyte cell death in
response to various stimuli [6, 7, 9].
GSK-3β is comprised of 12 exons in humans and 11 exons in mice with the ATG start codon located
within exon 1 and the TAG stop codon found in the terminal exon. The gene product is a 46 kDa protein
consisting of 433 amino acids in the human and 420 amino acids in the mouse. Figure 1 shows the
overall structure of GSK-3It is similar to other Ser/Thr kinases [10, 11]. The N-terminal domain is
comprised of the first 135 residues and forms a 7-strand -barrel motif. A small linker region connects
the N-terminal domain to the central α-helical domain formed by residues 139 through 342. The ATP
binding site lies at the interface of the N-terminal and α-helical domains. Residues 343 through 433 form
the C-terminal domain, which is outside of the classical Ser/Thr kinase core fold. These residues form a
helix/loop domain that interacts with the core α-helical domain. The N-terminal amino acids 78 through
92 are necessary for association with p53 (Figure 1). The activity of GSK-3 can be reduced by
phosphorylation at Ser-9. Several kinases are able to mediate this modification, including p70S6 kinase,
4. p90RSK, PKC and Akt [12, 13]. In opposition to the inhibitory phosphorylation of GSK3 at Ser-9,
phosphorylation of GSK-3 at Tyr-216 by ZAK1 or Fyn increases its enzyme activity [14] (Figure 2).
Dysregulation of GSK-3β expression leads to many pathological conditions, including diabetes (or insulin
resistance), neuronal dysfunction, Alzheimer’s disease [15-18], schizophrenia [19], Dopamine-associated
behaviors [20], bipolar disorders [21], Parkinson's disease [22] and cancer. Of special interest is the
involvement of GSK-3β in cancer with data supporting a role as a tumor suppressor and tumor
promoter, a discrepancy that at least in part depends on both cell type and signaling environment. For
example, GSK-3β has been shown to inhibit androgen receptor-stimulated cell growth in prostate
cancer, thus acting as a tumor suppressor [23]. In contrast, GSK-3β is highly expressed in colorectal
cancer [24, 25] and has been shown to participate in nuclear factor-κB (NF-κB)-mediated cell survival in
pancreatic cancer [26], thus behaving as a tumor promoter. Moreover, the kinase has dual functions in
the regulation of cell survival, where it can either activate or inhibit apoptosis [3, 27], further
complicating its involvement in cancer. This review will focus on how GSK-3β can both activate as well
as protect from apoptosis with a focus on oncology.
Regulation of -catenin levels is a critical step in Wnt signaling. β-Catenin is phosphorylated by GSK-3β
and then degraded through the ubiquitin-proteasome system [28-30]. Inhibition of GSK-3β activity leads
to stabilization and accumulation of β-catenin in the cytosol, which is shuttled into the nucleus and
regulates gene expression (Figure 2). GSK-3β is also involved in cell cycle regulation through the
phosphorylation of cyclin D1, which results in the rapid proteolytic turnover of cyclin D1 protein [1, 31]
(Figure 2). Direct overexpression of wild-type GSK-3 is known to induce apoptosis in various cell types
in culture, and specific inhibitors of GSK-3 are able to stop this apoptotic signaling [6, 7, 9, 32]. The
detailed molecular mechanism of GSK-3’s pro-apoptotic effect is as yet unknown, but it involves
regulation of metabolic and signaling proteins, transcription factors and gene expression [4, 33].
5. GSK-3β is required for proper development [4] and is ubiquitously expressed in the animal kingdom.
GSK-3β protein was originally isolated from skeletal muscle, but though widely expressed, the protein is
most abundant in brain tissue, especially neurons. The high level of expression in brain tissue is likely
due to its vital role in neuronal signaling. In neuronal cells, GSK-3β is required for dendrite extension and
synapse formation in newborns.
Regulation of Apoptosis by GSK-3
GSK-3β has been shown to induce apoptosis in a wide variety of conditions including DNA damage [34],
hypoxia [35], endoplasmic reticulum stress [36], and Huntington’s disease-associated polyglutamine
toxicity [37]. In cell culture studies, apoptosis was either attenuated or fully abrogated by inhibiting
GSK-3 in primary neurons [38], HT-22 cells [39], PC12 cells [40], and human SH-SY5Y neuroblastoma
cells [36, 41].
GSK-3 promotes apoptosis by inhibiting pro-survival transcription factors, such as CREB and heat shock
factor-1 [42], and facilitating pro-apoptotic transcription factors such as p53 [34]. A list of some
alternative conditions where GSK-3β facilitates apoptosis is given in Table 1. A large number of proteins
have been shown to interact with the tumor suppressor transcription factor p53 to regulate its actions
[43, 44], which has been implicated in the pro-apoptotic actions of GSK-3β in several studies. Following
DNA damage, the normally short-lived p53 protein is stabilized and modified by a complex array of
posttranslational modifications, such as phosphorylation, acetylation, methylation, ubiquitination,
sumoylation, glycosylation, and neddylation. One of these regulatory proteins is GSK-3β, which forms a
complex with nuclear p53 to promote p53-induced apoptosis [34, 45, 46]. GSK-3β binds directly to p53
and the C-terminal region of p53 is necessary for this interaction [45]. GSK-3β was shown to directly
phosphorylate p53 at Ser-33 [47], and to mediate p53 phosphorylation at Ser-315 and Ser-376 [48, 49].
GSK-3β also promotes p53-mediated transcription of specific genes and regulates the intracellular
6. localization of p53 [45, 46, 49]. In addition to GSK-3β regulating p53, GSK-3β is also regulated by p53.
The activity of GSK-3β is increased by a phosphorylation-independent mechanism of direct binding of
p53 to GSK-3β [34]. Nuclear localization of GSK-3β may also be regulated by binding of activated p53
[50].
In addition to direct interaction, GSK-3β can regulate p53 levels through the phosphorylation of the
p53-specific E3 ubiquitin ligase MDM2 [51]. Regulation of p53 by MDM2 is multifaceted. In the classical
model, N-terminal phosphorylation of p53 at Ser-15 (mouse Ser-18) and Ser-20 (mouse Ser-23) inhibits
the interaction with MDM2 and thereby prevents MDM2-mediated ubiquitination and the resulting
proteasomal degradation of p53 [44] (Figure 3). Stabilized p53 then enters a complex regulatory
network to induce DNA binding and transcriptional activation of p53 target genes, in part through the
recruitment of coactivators and corepressors. This determines the specific cellular response, which can
include survival, growth arrest, DNA repair or apoptosis [44]. Inhibition of GSK-3 in hippocampal
neurons protected it from radiation-induced apoptosis [9, 52]. Similar protection from GSK-3β inhibition
has been seen in primary neurons [38]. The mechanism of protection from radiation-induced apoptosis
in these cells involves subcellular localization and interaction of GSK3, p53, and MDM2. GSK-3
inhibition blocks radiation-induced accumulation of p53 by upregulating levels of MDM2 that
subsequently result in decreased radiation-dependent apoptosis [53]. In addition to abrogation of
radiation-induced p53 phosphorylation, accumulation, and nuclear translocation, GSK-3 inhibition
results in the accumulation of MDM2 and sequestration of GSK-3, p53, and MDM2 in the cytoplasm
where p53 cannot act on its target genes [53]. The role of attenuated p53 function in the pro-survival
effects of the GSK-3β inhibitors, have also been previously described [34, 46, 52, 54, 55].
In regulation of the apoptotic response, mammalian cells employ multiple pro-survival proteins from the
Bcl-2 family (Bcl-2, Bcl-XL, Bcl-w, Mcl1 and A1) that antagonize the pro-apoptotic function of Bax and Bak
7. [34, 56]. Bax and Bak localize to the mitochondrial outer membrane and trigger death signals leading to
cytochrome c release to the cytosol [56, 57]. Apoptosis requires a group of effector caspases to
dismantle the cells. Cytochrome c activates caspase-9, which subsequently activates caspase-3 [58]. The
activation of caspase-3 is an essential step leading to cleavage of the DNA repair enzyme, poly (ADP-
ribose) polymerase (PARP), resulting in genomic DNA fragmentation. Bax protein levels and cleavage
(activation) of caspase-3 were increased due to radiation and were abrogated by GSK-3β inhibitors [59]
(Figure 3). GSK-3β was also found to be associated with mitochondrial apoptotic signaling. Inhibition of
GSK-3β prevented mitochondrial release of cytochrome c, which is known to activate caspase -3 and
initiate apoptosis [34]. Phosphatidylinositol 3-kinase (PI3-kinase) and its downstream effector, the
protein-serine/threonine kinase Akt, a negative regulator of GSK-3β, play an important role in
preventing apoptosis by blocking activation of the caspase cascade[60].
Survival-Promoting Effects of GSK-3β
GSK-3β is involved in multiple signaling pathways and has many phosphorylation targets. It should
therefore not be surprising that GSK-3β has both pro- and anti-apoptotic roles. The overall effect of
GSK-3β on cell survival varies depending on cell type, transformation status, and the specific signaling
pathway being activated. For example, despite evidence for a substantial pro-apoptotic role of GSK-3β,
it is the inhibition of GSK-3β that promotes apoptosis and decreases viability in neuroblastoma cells [61].
Several examples of pro-survival roles of GSK-3β not mentioned here are summarized in Table 2 [62-66].
Additionally, while GSK-3β has been typically identified as an activator of p53-mediated apoptosis [34],
conflicting reports suggest an inhibitory effect of GSK-3β signaling on p53 activation. Inhibition of
GSK-3β blocks activation of MDM2 by reducing Ser-254 phosphorylation. This prevents p53 degradation
and promotes apoptosis despite the induction of p53 ubiqui tination . Similarly, ionizing radiation was
found to induce an inactivating phosphorylation at Ser-9 of GSK-3β, corresponding to
8. hypophosphorylation of MDM2 and accumulation of p53 [51]. In contrast to its pro-apoptotic effects,
this data suggests that GSK-3β inhibits apoptosis under basal conditions through MDM2-dependent
degradation of p53. Overexpression of β-catenin, a downstream signaling factor negatively regulated by
GSK-3β, was found to increase basal p53 levels by blocking both MDM2-dependent and independent
degradation in neuroblastoma cells [67], providing additional supporting evidence for an inhibitory
effect of GSK-3β on p53 mediated apoptosis. Interestingly, a negative feedback loop exists between
β-catenin and p53; while β-catenin upregulates p53 levels the activation of p53 results in degradation of
β-catenin through GSK-3β [68]. While the majority of publications suggest a pro-apoptotic role for GSK-
3β in p53 signaling, it is clear that more comprehensive studies are needed in order to fully understand
the p53-GSK-3β relationship.
GSK-3β is specifically required for hepatocyte survival in normal embryos, and GSK-3β knockout mice are
embryonically lethal between E13.15-14.5. Hepatocyte apoptosis in GSK-3β knockout mice and mouse
embryonic fibroblasts result only after exposure to tumor necrosis factor (TNF), while inhibition of
GSK-3β in wild-type cells with lithium increases TNF sensitivity. GSK-3β loss in these cells has a
detrimental effect on the action of NF-κB, which protects against TNF-induced apoptosis [69]. Other
studies have shown that GSK-3β directly promotes NF-κB stability and activation through both the
degradation of p105 and activation of the p65 subunit, suggesting a likely mechanism for
lithium-induced TNF hypersensitivity [70, 71] (Figure 3). The role of GSK-3β on NF-κB may also be
mediated indirectly through inhibition of β-catenin, as cancer cells with high β-catenin levels are
especially sensitive to TNF-induced death [72].
Despite the abundance of evidence implicating GSK-3β in protection from TNF-mediated apoptosis, a
few conflicting reports further complicate our understanding of the pathway. A more recent study
claims that GSK-3 inhibition does indeed reduce NF-κB activity but does not result in TNF-mediated
9. apoptosis, potentially due to the activation of pro-survival genes through Wnt signaling [73]. Similarly,
TNF sensitization by lithium in multiple sarcoma cell lines was found to be independent of both GSK-3β
and NF-B [74] while GSK-3β inhibition in prostate cancer and HEK cells actually increased NF-B activity
despite promoting TNF-induced apoptosis [75].
The specifics of apoptosis regulation by GSK-3β remain both ambiguous and complex, requiring further
research in order to determine the mechanisms of action responsible for differential control of cell
survival. In addition to variations in cell signaling and proliferation status, the effect of GSK-3β on
apoptosis may depend on cellular localization. Only cytosolic GSK-3β was found to inhibit TNF-mediated
apoptosis [62] while apoptosis enhances nuclear localization [76], suggesting a potential localization-
based mechanism for differential apoptotic regulation. Insufficient data is available to explain the
contradictory effects proposed for GSK-3β on p53-mediated apoptosis and a more detailed study is
required in order to determine the reasons for these observed differences, but differential localization
of p53, MDM2 and GSK-3β may help define the regulatory role of GSK-3β in various systems.
Positive Regulators of GSK-3β
Several molecules are known to potentiate the downstream effects of GSK-3β (Table 3). Positive
regulators ofGSK-3β are often utilized for enhancing the pro-apoptotic effects of GSK-3β in the context
of chemotherapy for cancer treatment (reviewed in [77]). These regulators typically operate through an
indirect mechanism, actually serving as inhibitors for upstream negative regulators. For example, GSK-3β
activity is increased upon inhibition of PI3-Kinase with wortmannin or LY294002 [78-80]. Many GSK-3β
regulators act to inhibit Akt by blocking its activation or kinase activity. The kinase inhibitor
staurosporine and the COX-2 inhibitor Celecoxib block the activating phosphorylation of Akt by PDK [81-
85]. Additionally, curcumin dephosphorylates Akt to prevent its downstream inactivation of GSK-3β [83],
as does the histone deacetylase inhibitor Trichostatin A, in a PP1-dependent manner [86]. Akt/protein
10. kinase B signaling inhibitor-2 (API-2) appears to suppress both Akt activation and kinase activity
independent of any upstream inhibitor effects [87].
Alternative GSK-3β regulators have less defined and more indirect mechanisms. The mTOR inhibitor
rapamycin has been shown to activate GSK-3β with some studies suggesting a potential influence of the
mTOR pathway on GSK-3β regulation through phosphorylation by s6 kinase [88, 89]. Other molecules
target the ability of GSK-3β to degrade cyclin D1. Vitamin A derived retinoids and multiple
differentiation-inducing factors (DIFs) enhance GSK-3β activation and kinase activity [90-93] as a means
for cyclin D inhibition to promote cell cycle arrest and differentiation.
Inhibitors of GSK-3
While a potential therapeutic role of GSK-3β inhibitors has been suggested for some time, they have
gained significant interest as a clinical tool over the past decade. GSK-3β inhibitors are currently being
utilized for the treatment of various diseases including Alzheimer’s disease [94, 95] and other
neurodegenerative diseases[18], diabetes, inflammatory disorders [96], radiation damage, and cancer
[97]. Various pharmaceutical companies have these inhibitors in clinical trials [97]. A classical example of
a non-specific GSK-3β inhibitor is lithium [21], which has been shown to inhibit GSK-3β with an IC50 of
approximately 2 mM in an uncompetitive manner with respect to peptide substrate. Lithium was found
to inhibit GSK-3β in a competitive manner by binding directly to magnesium binding sites of the enzyme
[98], thus providing evidence for a molecular mechanism for enzyme inactivation by lithium ions. Four
distinct regions of GSK-3 have been targeted for inhibition: the Mg2+ATP-binding active site, a separate
Mg2+-binding site, the substrate-binding groove and the scaffold-binding region [33, 99]. Several
inhibitors compete with Mg2+ and/or ATP to occupy its binding site. However, the specificity of these
inhibitors towards GSK-3 relative to other kinases varies significantly (Table 4). Structural studies have
11. further elucidated molecular mechanisms for substrate selection and GSK3-inhibition [100-106].
Beryllium was shown to compete with both ATP and Mg 2+, while lithium competed only with Mg2+ [107].
The small molecule inhibitors of GSK-3 SB-216763 and SB-415286 are structurally distinct maleimides
that inhibit GSK-3/ in vitro, with Kis of 9 nM and 31 nM respectively, in an ATP competitive manner
[108]. Hymenialdisine [109] and paullones [110] also inhibit GSK-3β in a ATP competitive manner.
Indirubins inhibit GSK-3β in a ATP competitive manner with a IC 50 of 50-100 nM [111-113]. Small
molecule inhibitors like TZDZ8 that are thiadiazolidinones inhibit GSK-3β with a IC50 of 2µM in a non
competitive manner [114, 115]. The other type of GSK-3 inhibitors is represented by cell-permeable,
phosphorylated substrate-competitive peptides which interact with the phospho-recognition motif
comprising R96, R180 and K205 to prevent substrate access to the active site. There are also
GSK-3-inhibiting peptides that contain GSK-3 interacting domains and block the interaction between
Axin and GSK-3 and prevent β-catenin phosphorylation [116]. In the recent decade small molecule
inhibitors of GSK-3β are emerging as a promising drug for treatments against neurodegenerative
diseases, radiation damage, Alzheimer’s disease, diabetes and cancer[97].
Exploiting the GSK-3β Conundrum
GSK-3β signaling is a complex process influenced not only by cellular type and transformation status, but
by environmental and cellular conditions. Survival signals have been mainly determined by studies
involving GSK-3β inhibition, through gene silencing or pharmacologic inhibition. The resulting inhibition
of apoptosis is complex, and requires further elucidation. However several studies suggest that the
effects may at least in part be mediated by the effect of GSK-3β on NF-κB levels. In addition, it is clear
that subcellular localization is important, as only cytosolic GSK-3β seems to be able to mediate the
survival signals.
12. Notably, the role in promotion of apoptosis by GSK-3β has been more clearly delineated. It performs this
task by both facilitating pro-apoptotic signals while inhibiting anti-apoptotic molecules. This signal
interplay occurs mostly at the level of the mitochondria, and combined with the association with
primarily nuclear GSK-3β, suggests a downstream role of GSK-3β in modulation.
So how do we exploit these paradoxical roles of GSK-3β? In healthy cells, the shift to pro-survival modes
is important for cell survival under conditions of cellular stress. In these cases, the upstream signals
seem to override the mitochondrial-based apoptotic machinery to allow the cells to escape potentially
lethal damage. There have been attempts to exploit these pro-survival roles in neurodegenerative
diseases, which are typified by high apoptosis rates. Reduction of disease -associated apoptosis by
GSK-3β modulating agents can restore balance to off-kilter apoptotic machinery, resulting in decreased
cellular turnover and the resultant protection of the at-risk neuronal population. In addition to diabetes,
and neurodegenerative disorders, we believe that GSK-3β inhibition may play a promising role in
patients receiving irradiation.
While radiation dose-escalation has been important for the treatment of multiple cranial tumors (e.g.
brain metastases, primary gliomas) and benign disorders (e.g. vestibular schwannoma, meningioma),
the treatment is limited by the effects of irradiation on healthy surrounding neurons. It has been
demonstrated that GSK-3β inhibition can protect hippocampal neurons (in primary culture and murine
pups) from irradiation-induced damage [9, 52]. Thotala et al. demonstrated improved survival of
intestinal crypt cells, and increased latency to murine GI-related death from irradiation [59]. This report
suggested that GSK-3β inhibitors could reduce deleterious consequences of intestinal irradiation, and
possibly improve patient quality of life measures. It would be worthwhile to explore their utility in
syngenic murine models of neural cancer, murine tumor xenografts, as well as human clinical trials of
13. patients in the setting of re-irradation (e.g. recurrent glioma). Reports of radiation protection have also
been demonstrated with small molecular inhibitors of GSK-3β in the gastrointestinal system.
In cancer, however, the apoptotic machinery is often defective allowing cells to undergo unregulated
proliferation. In this case, negative regulation of GSK-3β can serve to tip the balance in favor of
apoptosis. Dickey et al. demonstrated the ability of GSK-3β inhibition to effectively enhance cell death of
neuroblastoma cells in vitro and in a murine xenograft model [61]. Similar findings have been
demonstrated in glioma [63, 64]. The interplay between GSK-3β regulation and other cell death stimuli is
being carefully studied across a wide variety of cancer types, and there is promising data suggesting a
strong role for this form of therapy in the near future. The bifunctional role of GSK-3β as a facilitator of
apoptosis and a mediator of pro-survival signals has important implications in both the generation of
novel therapies, and the understanding of complex disease states.
The use of both positive and negative regulators of GSK-3β offer exciting treatment possibilities for a
multitude of diseases. The complexity of the GSK-3β network requires careful examination however
when considering modulating its function in a clinical setting. More studies are required to clearly
understand the effects of regulating GSK-3β on the multiple signaling pathways involved in growth,
development and metabolism. The effect of GSK-3β on cell survival and apoptosis appears to be context
dependent, and the required mode of action will likely depend on the specific pathway, cell type and
disease being targeted. While the vast network of GSK-3β offers a treatment option for multiple
diseases it also requires careful consideration of all the factors involved in order to prepare against
potential side effects.
14. Table 1. Conditions where GSK-3β facilitates apoptosis.
System or Stimulus Mechanism
C(2) Ceramide-associated Inhibits the phosphorylation of AKT and ERK pathways and
damage through the dephosphorylation of GSK-3β[117]. GSK-3β inhibitors
have been shown to inhibit apoptosis through inhibiting
dephosphorylation of AKT and GSK-3β [118].
LPS mediated endotoxic shock While specific apoptotic studies have not been performed, LPS has
been shown to stabilize apoptotic signal-regulating kinase-1
(ASK-1), a serine-threonine kinase associated with stress-induced
apoptosis [119]
Immune System Regulates in apoptosis of activated T-Cells [120]
HIV-mediated neuronal damage Inhibits NF-κB [121-123]
Neurodegenerative Neuronal or oligodendrocyte injury or toxicity (including prion
disease-related toxicity and peptide) is associated with increased activity of GSK-3β. [117, 124-130]
Oxidative stress Negative regulators of GSK-3B are associated with increased
survival factors [117, 124-130] and neuroprotection[9, 38]
ER Stress ER-Stress can lead to dephosphorylation of pGSK-3β(S9), leading to
stress-induced apoptosis through activated caspase-3[12-14, 26, 28]
Hypoxia/Ischemia Activates mitochondrial death pathway [35, 131-134]
15. Table 2. Other Pro-survival roles of GSK-3β.
System Mechanism
ER stress Reduces expression of the pro-apoptotic transcription factor
CHOP/GADD153 [135]
Glioblastoma differentiation Promotes self-renewal through interaction with Bmi1 [63]
Death receptor complex Inhibits apoptotic signaling and caspase activation [65]
Chemotherapy Targeting by death-inducing drugs suggesting an inhibitory role
[66]
Oncogenic activation Inhibits apoptotic activation by c-myc [64]
Glucose Metabolism Prevents apoptosis through mitochondrial stabilization [64]
16. Table 3. List of known positive regulators of GSK-3β
Activator Activation Potency Mode of Activation Notes
Inhibits PDK
Celecoxib IC50 = 3.5µM phosphorylation of Akt COX-2 inhibitor [81]
General kinase
Inhibits PDK inhibitor (including
Staurosporine IC50 = 0.22µM phosphorylation of Akt PKA/PKC) [82, 84, 85]
Induces Akt HDAC inhibitor, acts
Trichostatin A Unknown dephosphorylation through PP1 [86]
Direct target not
Circumin Unknown AKT dephosphorylation known [83]
Akt/protein kinase B Does not affect
signaling inhibitor-2 Suppresses Akt kinase upstream Akt
(API-2) Unknown activity and activation activators [87]
Indirect effect on
Wortmannin IC50 = 5nM Inhibits PI3-Kinase GSK-3B [78, 79]
Likely affects ATP
LY294002 IC50 = 1.4µM Inhibits PI3-Kinase binding to kinase [79, 80]
mTOR pathway can
Rapamycin Unknown Potentially inhibits S6K1 also inhibit GSK3 [88, 89]
Reduces inhibitory
Enhances GSK-3β kinase phosphorylation and
Differentiation- activity and promotes enhances activating
inducing factors (DIFs) Unknown nuclear localization phosphorylation [92, 93]
Promotes
Reduces inhibitory GSK-3β-dependent
phosphorylation of cyclin D1 degradation
[62, 90]
Retinoids Unknown GSK-3β
17. Table 4. Selected list of known GSK-3 inhibitors.
Inhibitor Inhibition potency Mode of Inhibition Notes
Beryllium IC50 = 6 mM Mg competitor Also inhibits cdc2
Lithium Ki=2 mM Mg competitor
Does not inhibit a
Anilino maleimides (SB216763,
Ki = 10-30 nM ATP competitor range of other
SB415286)
kinases
Arylpyrazolopyridazines (e.g. 6-aryl Also inhibits
IC50 = 0.8-150 nM ATP competitor
pyrazole [3,4-b] byridine 4) CDK2
Bisindole maleimides (e.g. Ro
IC50 = 5-170 nM ATP competitor Also inhibits PKC
31-8220, GF 109203x)
Indirubins (6-bromoindirubin-3’- Also inhibits
IC50 = 5-50 nM ATP competitor
oxime, aka BIO) CDKs
Also inhibits
Paullones (alsterpaullone) IC50 = 4-80 nM ATP competitor
CDKs
Substrate
Pseudosubstrate peptide Ki = 0.7 mM Specific
competitor
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26. Basic Domain
S9
Y216
NH2 COOH
p53 Association
Figure 1: Glycogen synthase kinase-3β (GSK-3β) structure. Above: GSK-3β is a 433 residue protein
consisting of 3 distinct structural domains. The N-terminal domain (yellow) consists of the first 134
residues and forms a 7-strand β-barrel. A short linker from the N-terminal domain, residues 135-151
connect the N-terminal domain to the α-helical domain (magenta). The α-helical domain is composed of
residues 152-342. Sandwiched between the N-terminal and -helical domain is the ATP binding site. The
C- terminal domain consists of residues 343-433 (blue). Below: A strand diagram of GSK-3.
Phosphorylation of Ser-9 inactivates the enzyme, while phosphorylation of Tyr-216 activates. The p53
association region and basic domain region are both located in the N-terminal domain. Image was made
using PyMol Molecular Graphics Software version 1.3 with the PDB structure 1UV5.
27. Figure 2: Regulation of GSK-3β. GSK-3β is a multifunctional kinase that has a role in various signaling
pathway that regulate cell fate. ZAK1 or Fyn can phosphorylate Tyr-216 which increases the GSK-3β
activity. GSK-3β can phosphorylate downstream targets like β-catenin and degrade it through the
ubiquitin-proteasome system. Akt and PKC on the other hand can attenuate GSK-3β enzymatic activity
by phosphorylating Ser-9. Inhibition of GSK-3β activity therefore leads to stabilization and accumulation
of β-catenin in the cytosol, which is shuttled into the nucleus where it functions to regulate gene
expression. GSK-3β is also involved in cell cycle regulation through the phosphorylation of cyclin D1,
which results in the rapid proteolytic turnover of cyclin D1 protein.
28. Figure 3: GSK-3β’s role in apoptosis signaling. The above schematic shows the role of activated GSK-3β
and its role in regulating apoptosis. Active GSK-3β inhibits MDM2 regulation of p53, leading to DNA
repair and growth arrest, and in some cases the activation of the caspase cascade through Bax to
promote apoptosis. Active GSK-3β also positively regulates NFB by activating IKK, IB and p65, leading
to the inhibition of TNF-mediated apoptosis. These actions inhibit the initiation of apoptosis through the
TNF signaling caspase. Conversely, inactivation of GSK-3β leads to accumulation of β-catenin that is
transported into the nucleus for WNT signaling to further promote cell survival.