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https://www.readbyqxmd.com/read/29235570/targeting-negative-regulation-of-p53-by-mdm2-and-wip1-as-a-therapeutic-strategy-in-cutaneous-melanoma
#1
Chiao-En Wu, Arman Esfandiari, Yi-Hsuan Ho, Nan Wang, Ahmed Khairallah Mahdi, Erhan Aptullahoglu, Penny Lovat, John Lunec
BACKGROUND: Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29235380/pharmacokinetic-drug-evaluation-of-ixazomib-citrate-for-the-treatment-of-multiple-myeloma
#2
Marco Salvini, Rossella Troia, Davide Giudice, Chiara Pautasso, Mario Boccadoro, Alessandra Larocca
multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients...
December 13, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29234671/a-new-role-for-the-nuclear-basket-network
#3
COMMENT
Paola Gallardo, Silvia Salas-Pino, Rafael R Daga
Our view of the nuclear pore complexes (NPCs) as gateways between the nuclear and cytoplasmic compartments has been largely expanded in recent years. NPCs have now demonstrated roles in genome regulation and maintenance from single cells to multicellular organisms. Both NPC proteins as well as components of the NPC basket act as dynamic scaffolds for silencing factors, and chromatin and cell cycle regulators. Components of the NPC basket also couple mRNA production and export, and prevent the exit of unprocessed mRNAs from the nucleus...
November 27, 2017: Microbial Cell
https://www.readbyqxmd.com/read/29234123/dusp1-regulates-apoptosis-and-cell-migration-but-not-the-jip1-protected-cytokine-response-during-respiratory-syncytial-virus-and-sendai-virus-infection
#4
Alexa C Robitaille, Elise Caron, Nicolas Zucchini, Espérance Mukawera, Damien Adam, Mélissa K Mariani, Anaïs Gélinas, Audray Fortin, Emmanuelle Brochiero, Nathalie Grandvaux
The host antiviral response involves the induction of interferons and proinflammatory cytokines, but also the activation of cell death pathways, including apoptosis, to limit viral replication and spreading. This host defense is strictly regulated to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Post-translational modifications, most notably phosphorylation, are key regulators of the antiviral defense implying an important role of protein phosphatases. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the host defense against human respiratory syncytial virus (RSV), a pathogenic virus of the Pneumoviridae family, and Sendai virus (SeV), a model virus being developed as a vector for anti-RSV vaccine...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29233968/hrd1-prevents-apoptosis-in-renal-tubular-epithelial-cells-by-mediating-eif2%C3%AE-ubiquitylation-and-degradation
#5
Yujie Huang, Yifei Sun, Yizhi Cao, Hui Sun, Min Li, Hui You, Dongming Su, Yanjiao Li, Xiubin Liang
Apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. One factor that regulates important cellular processes like apoptosis and cell proliferation is HRD1, an E3 ubiquitin ligase that acts by promoting ubiquitylation and degradation of its target protein. However, the detailed mechanisms by which HRD1 acts as a regulator of apoptosis in renal tubular epithelial cells have not been established. In our previous liquid chromatography-tandem mass spectrometry (LC-MS/MS) study (Mol Endocrinol...
December 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29233916/aging-impairs-both-primary-and-secondary-rig-i-signaling-for-interferon-induction-in-human-monocytes
#6
Ryan D Molony, Jenny T Nguyen, Yong Kong, Ruth R Montgomery, Albert C Shaw, Akiko Iwasaki
Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid-inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors...
December 12, 2017: Science Signaling
https://www.readbyqxmd.com/read/29233753/targeting-the-26s-proteasome-to-protect-against-proteotoxic-diseases
#7
REVIEW
Natura Myeku, Karen E Duff
Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction...
December 9, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29232559/cilostazol-a-phosphodiesterase-3-inhibitor-activates-proteasome-proteolysis-and-attenuates-tauopathy-and-cognitive-decline
#8
Ari W Schaler, Natura Myeku
Alzheimer's disease and several variants of frontotemporal degeneration including progressive supranuclear palsy and corticobasal degeneration are characterized by the accumulation of abnormal tau protein into aggregates. Most proteins, including tau, are degraded via the ubiquitin proteasome system, but when abnormal tau accumulates, the function of 26S proteasomes is downregulated. The negative effect of tau aggregates on the function of the proteasome can have deleterious consequences on protein homeostasis and disease progression...
November 23, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/29231806/a-picorna-like-virus-suppresses-the-n-end-rule-pathway-to-inhibit-apoptosis
#9
Zhaowei Wang, Xiaoling Xia, Xueli Yang, Xueyi Zhang, Yongxiang Liu, Di Wu, Yuan Fang, Yujie Liu, Jiuyue Xu, Yang Qiu, Xi Zhou
The N-end rule pathway is an evolutionarily conserved proteolytic system that degrades proteins containing N-terminal degradation signals called N-degrons, and has emerged as a key regulator of various processes. Viruses manipulate diverse host pathways to facilitate viral replication and evade antiviral defenses. However, it remains unclear if viral infection has any impact on the N-end rule pathway. Here, using a picorna-like virus as a model, we found that viral infection promoted the accumulation of caspase-cleaved Drosophila Inhibitor of Apoptosis 1 (DIAP1) by inducing the degradation of N-terminal amidohydrolase 1 (NTAN1), a key N-end rule component that identifies N-degron to initiate the process...
December 12, 2017: ELife
https://www.readbyqxmd.com/read/29231132/functional-regulation-of-proteins-by-20s-proteasome-proteolytic-processing
#10
Maya A Olshina, Gili Ben-Nissan, Michal Sharon
No abstract text is available yet for this article.
December 12, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29229809/proteasomes-tether-to-two-distinct-sites-at-the-nuclear-pore-complex
#11
Sahradha Albert, Miroslava Schaffer, Florian Beck, Shyamal Mosalaganti, Shoh Asano, Henry F Thomas, Jürgen M Plitzko, Martin Beck, Wolfgang Baumeister, Benjamin D Engel
The partitioning of cellular components between the nucleus and cytoplasm is the defining feature of eukaryotic life. The nuclear pore complex (NPC) selectively gates the transport of macromolecules between these compartments, but it is unknown whether surveillance mechanisms exist to reinforce this function. By leveraging in situ cryo-electron tomography to image the native cellular environment of Chlamydomonas reinhardtii, we observed that nuclear 26S proteasomes crowd around NPCs. Through a combination of subtomogram averaging and nanometer-precision localization, we identified two classes of proteasomes tethered via their Rpn9 subunits to two specific NPC locations: binding sites on the NPC basket that reflect its eightfold symmetry and more abundant binding sites at the inner nuclear membrane that encircle the NPC...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29229304/functional-characterization-of-the-g162r-and-d216h-genetic-variants-of-human-cyp17a1
#12
C P Capper, J Liu, L R McIntosh, J M Larios, M D Johnson, P F Hollenberg, Y Osawa, R J Auchus, J M Rae
Cytochrome P450 17A1 (CYP17A1) is a dual-function enzyme catalyzing reactions necessary for cortisol and androgen biosynthesis. CYP17A1 is a validated drug target for prostate cancer as CYP17A1 inhibition significantly reduces circulating androgens and improves survival in castration-resistant prostate cancer. Germline CYP17A1 genetic variants with altered CYP17A1 activity manifesting as various endocrinopathies are extremely rare; however, characterizing these variants provides critical insights into CYP17A1 protein structure and function...
December 8, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29229189/immunoproteasome-inhibition-prevents-chronic-antibody-mediated-allograft-rejection-in-renal%C3%A2-transplantation
#13
Jun Li, Michael Basler, Gerardo Alvarez, Thomas Brunner, Christopher J Kirk, Marcus Groettrup
Chronic antibody-mediated rejection is the major cause of fading allograft function and loss after renal transplantation. Currently, pharmacological agents for the suppression of chronic antibody-mediated rejection are lacking. Non-selective proteasome inhibitors suppress antibody-mediated allograft rejection. However, extensive adverse side effects of these inhibitors severely limit their application. In contrast, immunoproteasome inhibition is effective in preclinical models of autoimmune diseases and was applied over weeks without obvious adverse side effects...
December 4, 2017: Kidney International
https://www.readbyqxmd.com/read/29228593/proteasome-inhibitor-bortezomib-enhances-the-effect-of-standard-chemotherapy-in-small-cell-lung-cancer
#14
Sanaz Taromi, Florentine Lewens, Ruza Arsenic, Dagmar Sedding, Jörg Sänger, Almut Kunze, Markus Möbs, Joana Benecke, Helma Freitag, Friederike Christen, Daniel Kaemmerer, Amelie Lupp, Mareike Heilmann, Hedwig Lammert, Claus-Peter Schneider, Karen Richter, Michael Hummel, Britta Siegmund, Meike Burger, Franziska Briest, Patricia Grabowski
Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29226967/gender-specific-expression-of-gibberellic-acid-insensitive-is-critical-for-unisexual-organ-initiation-in-dioecious-spinacia-oleracea
#15
Nicholas W West, Edward M Golenberg
While unisexual flowers have evolved repeatedly throughout angiosperm families, the actual identification of sex-determining genes has been elusive, and their regulation within populations remains largely undefined. Here, we tested the mechanism of the feminization pathway in cultivated spinach (Spinacia oleracea), and investigated how this pathway may regulate alternative sexual development. We tested the effect of gibberellic acid (GA) on sex determination through exogenous applications of GA and inhibitors of GA synthesis and proteasome activity...
December 11, 2017: New Phytologist
https://www.readbyqxmd.com/read/29226956/analysis-of-secreted-peptidome-from-omental-adipose-tissue-in-polycystic-ovarian-syndrome-patients
#16
Genmei Jia, Hongjiang Tao, Yunping Xue, Sujuan Xu, Kai Xue, Qiaoying Zhu, Xiaoyan Chen, Qian Li, Pengfei Xu
Polycystic Ovarian Syndrome (PCOS) is a common endocrinopathy associated with increased risk of metabolic disorders. Prevalence of adiposity and obesity is greater in women suffering from PCOS. Moreover, adipose tissue dysfunction has been demonstrated in PCOS patients, particularly in abdominal adipose tissue. This dysfunction likely aggravates the metabolic and reproductive abnormalities. We used liquid chromatography-mass spectrometry to compare the peptides secreted from PCOS and non-PCOS abdominal adipose tissue...
December 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29226427/case-report-treatment-of-light-chain-amyloidosis-with-daratumumab-monotherapy-in-two-patients
#17
Charlotte Gran, Gösta Gahrton, Evren Alici, Hareth Nahi
Immunoglobulin light-chain amyloidosis (AL) affects multiple organs, most prominently the kidney and the heart. Renal and cardiac impairment are both associated with poor prognosis.(1) Typical treatment regimens for AL include proteasome inhibitors, alkylating agents, and steroids as well as autologous stem cell transplantation (ASCT) for younger, fit patients. Complete response after treatment is associated with a better outcome and can be measured by free light chain (FLC) reduction.(2, 3) Monoclonal antibodies such as daratumumab (Dara, human IgG1 anti-CD38) have shown promising efficacy for the treatment of relapsed and refractory multiple myeloma...
December 11, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29225318/caffeine-stimulated-intestinal-epithelial-cells-suppress-lipid-accumulation-in-adipocytes
#18
Takakazu Mitani, Tomoya Nagano, Kiyonari Harada, Yoko Yamashita, Hitoshi Ashida
Caffeine is a methylxanthine derived from plant foods such as coffee beans and tea leaves, and has multiple biological activities against physiological response and several diseases. Although there are some reports about the direct effect of caffeine against anti-lipid accumulation in vitro, the effect of caffeine on lipid accumulation in adipocytes through stimulating intestinal epithelial cells is unknown. Since direct treatment with caffeine to 3T3-L1 cells did not affect lipid accumulation, we determined whether caffeine-stimulated intestinal epithelial Caco-2 cells influence the lipid accumulation in 3T3-L1 adipocytes...
2017: Journal of Nutritional Science and Vitaminology
https://www.readbyqxmd.com/read/29225035/cockayne-s-syndrome-a-and-b-proteins-regulate-transcription-arrest-after-genotoxic-stress-by-promoting-atf3-degradation
#19
Alexey Epanchintsev, Federico Costanzo, Marc-Alexander Rauschendorf, Manuela Caputo, Tao Ye, Lise-Marie Donnio, Luca Proietti-de-Santis, Frederic Coin, Vincent Laugel, Jean-Marc Egly
Cockayne syndrome (CS) is caused by mutations in CSA and CSB. The CSA and CSB proteins have been linked to both promoting transcription-coupled repair and restoring transcription following DNA damage. We show that UV stress arrests transcription of approximately 70% of genes in CSA- or CSB-deficient cells due to the constitutive presence of ATF3 at CRE/ATF sites. We found that CSB, CSA/DDB1/CUL4A, and MDM2 were essential for ATF3 ubiquitination and degradation by the proteasome. ATF3 removal was concomitant with the recruitment of RNA polymerase II and the restart of transcription...
November 30, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29224095/sex-differences-in-muscle-wasting
#20
Lindsey J Anderson, Haiming Liu, Jose M Garcia
With aging and other muscle wasting diseases, men and women undergo similar pathological changes in skeletal muscle: increased inflammation, enhanced oxidative stress, mitochondrial dysfunction, satellite cell senescence, elevated apoptosis and proteasome activity, and suppressed protein synthesis and myocyte regeneration. Decreased food intake and physical activity also indirectly contribute to muscle wasting. Sex hormones also play important roles in maintaining skeletal muscle homeostasis. Testosterone is a potent anabolic factor promoting muscle protein synthesis and muscular regeneration...
2017: Advances in Experimental Medicine and Biology
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