scholarly journals Deletion and overexpression of the scaffolding protein IQGAP1 promotes HCC

2020 ◽  
Author(s):  
Evan R Delgado ◽  
Hanna L Erickson ◽  
Junyan Tao ◽  
Satdarshan P Monga ◽  
Andrew W Duncan ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Tumor Burden ◽  
The Other ◽  
Scaffolding Protein ◽  
Gtpase Activating Protein ◽  
Liver Carcinogenesis ◽  
Tumor Target ◽  
Iq Motif ◽  
Multiple Signaling

AbstractIQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with many pro-tumorigenic processes including cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective anti-tumor target. Therefore, we examined the role for IQGAP1 in tumor initiation and promotion during liver carcinogenesis. Unexpectedly, we found that Iqgap1-/- mice had a higher tumor burden than Iqgap1+/+ and Iqgap1+/- mice following DEN-induced liver carcinogenesis. Iqgap1-/- tumors as well as knocking down IQGAP1 in hepatocellular carcinoma (HCC) cell lines resulted in increased MET activation and cellular proliferation. On the other hand, we uncovered IQGAP1 overexpression accelerates HCC development by YAP activation and subsequent NUAK2 expression. We demonstrate that increasing IQGAP1 expression in vivo does not alter β-catenin or MET activation. Taken together, we identify that both loss and gain of function of IQGAP1 promotes HCC development by two separate mechanisms in the liver. These results demonstrate that adequate amount of IQGAP1 is necessary to maintain a quiescent status of liver.

scholarly journals Scaffolding Protein IQGAP1 is Dispensable But Its Overexpression Promotes Hepatocellular Carcinoma via YAP1 Signaling

2021 ◽  
Author(s):  
Evan R Delgado ◽  
Hanna L Erickson ◽  
Junyan Tao ◽  
Satdarshan P Monga ◽  
Andrew W Duncan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Rapid Onset ◽  
Tumor Burden ◽  
Scaffolding Protein ◽  
Liver Carcinogenesis ◽  
Tumor Target ◽  
Iq Motif ◽  
Multiple Signaling

IQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with pro-tumorigenic processes such as cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective anti-tumor target. Therefore, we examined the role for IQGAP1 in tumor initiation and promotion during liver carcinogenesis. We found that ectopic overexpression of IQGAP1 in the liver is not sufficient to initiate tumorigenesis. Moreover, the tumor burden and cell proliferation in the DEN-induced liver carcinogenesis model in Iqgap1-/- mice maybe driven by MET signaling. In contrast, IQGAP1 overexpression enhanced YAP activation and subsequent NUAK2 expression to accelerate and promote hepatocellular carcinoma (HCC) in a clinically relevant model expressing activated (S45Y) β-catenin and MET. Here, increasing IQGAP1 expression in vivo does not alter β-catenin or MET activation; instead, it promotes YAP activity. Overall, we demonstrate that although IQGAP1 expression is not required for HCC development, the gain of IQGAP1 function promotes the rapid onset and increased liver carcinogenesis. Our results show that an adequate amount of IQGAP1 scaffold is necessary to maintain the quiescent status of the liver.

scholarly journals GENOTOXIC AND CARCINOGENIC STUDIES OF NORGESTREL IN DROSOPHILA MELANOGASTER

2018 ◽  
Vol 11 (10) ◽  
pp. 372
Author(s):  
Abou-eisha A ◽  
Adel E El-din
Keyword(s):  
Somatic Mutation ◽  
Cellular Proliferation ◽  
Research Work ◽  
The Body ◽  
The Other ◽  
Direct Stimulation ◽  
Carcinogenic Activity ◽  
Genetic Examination ◽  
First Time

Objective: The aim of this study was to investigate, for the first time, the possible in vivo genotoxic and carcinogenic activity associated with exposure to norgestrel (NGT) drug through employing the very recently established and adjusted genotoxic and tumorigenic methods in Drosophila melanogaster.Methods: Two in vivo genotoxic test systems were used; one detects the somatic mutation and recombination effects (somatic mutation and recombination test [SMART] wing-spot test) and the other detects the primary DNA damage (the comet test) in the body cells of D. melanogaster. On the other hand, the warts (wts)-based SMART assay is a vital genetic examination in Drosophila used to identify and characterize cancer potential of compounds.Results: Four experimental doses of NGT were used (ranging from 0.24 μM to 16 μM). NGT was found to be non-genotoxic at all tested concentrations even at the highest dose level 16 μM and failed to increase the frequency of tumors in the somatic cells of D. melanogaster.Conclusion: Our results strengthen the hypothesis that steroidal drugs might act through a non-genotoxic carcinogen mechanism where the carcinogenic properties occur by direct stimulation of cellular proliferation through a steroid receptor-mediated mechanism. In addition, the results obtained in this research work may contribute to highlighting the importance of NGT as a potent neuroprotective antioxidant drug.

scholarly journals PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma

2019 ◽  
Vol 216 (5) ◽  
pp. 1120-1134 ◽  
Author(s):  
Yong Jae Shin ◽  
Jason K. Sa ◽  
Yeri Lee ◽  
Donggeon Kim ◽  
Nakho Chang ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Cellular Proliferation ◽  
Negative Regulator ◽  
Bona Fide ◽  
Xenograft Models ◽  
Phosphoinositide 3 Kinase ◽  
Multiple Signaling ◽  
First Time

Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.

A Quantitative Analysis of the Effects of the Intraneural Injection of Lysophosphatidyl Choline

1973 ◽  
Vol 13 (1) ◽  
pp. 257-277
Author(s):  
N. A. GREGSON ◽  
SUSAN M. HALL
Keyword(s):  
Quantitative Analysis ◽  
Peripheral Nerves ◽  
Cellular Proliferation ◽  
The Other ◽  
Axon Diameter ◽  
Acid Moiety ◽  
Lysophosphatidyl Choline ◽  
Adult Mice ◽  
Intraneural Injection

Some quantitative aspects of the demyelinating lesion, and its progress, produced by the in vivo injection of lysophosphatidyl choline (LPC) into the myelinated peripheral nerves of adult mice have been investigated. The extent of the lesion has been shown to be highly localized to the injection site and dependent on the concentration of LPC. The length of the demyelinating zone appears to be determined within the first hour following the injection. The resulting demyelination occurs in units of whole internodes and over 40% of the fibres involved show the loss of only one internode. The length of the demyelinated zone does not show any obvious dependency on axon diameter. Remyelination has started by day 14 and involves on average the replacement of each original internode by 2 new segments. There is a cellular proliferation in response to the injection, starting within the first week and achieving a maximum between 2-3 weeks. Of the extra cells 70-80% are not axon-associated and of these 50% are supernumary Schwann cells. The use of 14C-oleate and 3H-stearyl LPC indicates that the injected LPC can be converted into lecithin, but also that the fatty acid moiety of LPC becomes distributed amongst the other lipid classes. Pretreatment of the nerve with small amounts of KCN blocks the metabolism of the injected LPC and renders all of the cells subject to lysis.

Scaffolding Protein IQ Motif Containing GTPase Activating Protein 2 Regulates Liver Metabolic Homeostasis

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Anuhna Sen ◽  
Sara Youssef ◽  
Karen Wendt ◽  
Valentina Schmidt ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Scaffolding Protein ◽  
Metabolic Homeostasis ◽  
Gtpase Activating Protein ◽  
Iq Motif

scholarly journals Scaffolding protein IQ motif containing GTPase activating protein 2 (IQGAP2) regulates glycogen metabolism

2020 ◽  
Author(s):  
Anushna Sen ◽  
Sara Youssef ◽  
Karen Wendt ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Metabolic Response ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Scaffolding Protein ◽  
Gtpase Activating Protein ◽  
Fed State ◽  
Iq Motif ◽  
Protein Levels ◽  
Expression Of Genes

AbstractThe liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes of fats, proteins, and carbohydrates. The IQ motif containing GTPase activating protein 2 (IQGAP2) is a member of the IQGAP family. Of the three homologous isoforms, the IQGAP2 scaffolding protein is predominantly found in the liver. To characterize its role in regulating metabolism, Iqgap2−/− female and male mice, and their WT controls, were fed ad libitum or fasted for 24 hours. Hepatic gene expression, protein levels, and the metabolic response were compared between WT and Iqgap2−/− mice, using RT-qPCR, western blot analysis, and histological stains. We found that loss of IQGAP2 alters the phosphorylation of active glycogen synthase kinase 3 (GSK3) expression, a known regulator of glycogen synthesis and lipogenesis. Consistent with this result, Iqgap2−/− female mice displayed depletion of periportal glycogen even in the fed state. We also observed the blunted expression of genes involved in glycogenesis and lipogenesis when IQGAP2 was deleted. Since GSK3 is known to regulate the activity of β-catenin, we examined and found it to be reduced in Iqgap2−/− mice. Our findings demonstrate that IQGAP2 plays an important role in regulating glycogen synthesis.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

Oxytocin analogues with non-coded amino acid residues in position 8: [8-Neopentylglycine]oxytocin and [8-cycloleucine]oxytocin

1987 ◽  
Vol 52 (9) ◽  
pp. 2317-2325 ◽  
Author(s):  
Jan Hlaváček ◽  
Jan Pospíšek ◽  
Jiřina Slaninová ◽  
Walter Y. Chan ◽  
Victor J. Hruby
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
The Other ◽  
Amino Acid Residues ◽  
Phase Synthesis ◽  
Other Hand ◽  
Fragment Condensation

[8-Neopentylglycine]oxytocin (II) and [8-cycloleucine]oxytocin (III) were prepared by a combination of solid-phase synthesis and fragment condensation. Both analogues exhibited decreased uterotonic potency in vitro, each being about 15-30% that of oxytocin. Analogue II also displayed similarly decreased uterotonic potency in vivo and galactogogic potency. On the other hand, analogue III exhibited almost the same potency as oxytocin in the uterotonic assay in vivo and in the galactogogic assay.

scholarly journals An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Janire Urrutia ◽  
Alejandra Aguado ◽  
Carolina Gomis-Perez ◽  
Arantza Muguruza-Montero ◽  
Oscar R. Ballesteros ◽  
...  
Keyword(s):  
Structural Instability ◽  
Binding Assays ◽  
Iq Motif ◽  
Channel Function ◽  
Human Epilepsy ◽  
Pathogenic Variants ◽  
In Silico Studies ◽  
Nascent Chain

Abstract Background The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. Results We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. Conclusions Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitro.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

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