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https://www.readbyqxmd.com/read/28475871/aging-triggers-cytoplasmic-depletion-and-nuclear-translocation-of-the-e3-ligase-mahogunin-a%C3%A2-function-for-ubiquitin-in-neuronal-survival
#1
Stefano Benvegnù, María Inés Mateo, Ernest Palomer, Jerónimo Jurado-Arjona, Carlos G Dotti
A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28465486/overexpression-of-sphk2-contributes-to-atra-resistance-in-colon-cancer-through-rapid-degradation-of-cytoplasmic-rxr%C3%AE-by-k48-k63-linked-polyubiquitination
#2
Wen-Na Shi, Shu-Xiang Cui, Zhi-Yu Song, Shu-Qing Wang, Shi-Yue Sun, Xin-Feng Yu, Ye Li, Yu-Hang Zhang, Zu-Hua Gao, Xian-Jun Qu
The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28441528/phosphorylation-of-neurog3-links-endocrine-differentiation-to-the-cell-cycle-in-pancreatic-progenitors
#3
Nicole A J Krentz, Dennis van Hoof, Zhongmei Li, Akie Watanabe, Mei Tang, Cuilan Nian, Michael S German, Francis C Lynn
During pancreatic development, proliferating pancreatic progenitors activate the proendocrine transcription factor neurogenin 3 (NEUROG3), exit the cell cycle, and differentiate into islet cells. The mechanisms that direct robust NEUROG3 expression within a subset of progenitor cells control the size of the endocrine population. Here we demonstrate that NEUROG3 is phosphorylated within the nucleus on serine 183, which catalyzes its hyperphosphorylation and proteosomal degradation. During progression through the progenitor cell cycle, NEUROG3 phosphorylation is driven by the actions of cyclin-dependent kinases 2 and 4/6 at G1/S cell-cycle checkpoint...
April 24, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28400504/cardiopulmonary-phenotype-associated-with-human-phd2-mutation
#4
Nick P Talbot, Thomas G Smith, George M Balanos, Keith L Dorrington, Patrick H Maxwell, Peter A Robbins
Oxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia...
April 2017: Physiological Reports
https://www.readbyqxmd.com/read/28380042/genetic-and-pharmacological-inhibition-of-ttk-impairs-pancreatic-cancer-cell-line-growth-by-inducing-lethal-chromosomal-instability
#5
Jeran K Stratford, Feng Yan, Rebecca A Hill, Michael B Major, Lee M Graves, Channing J Der, Jen Jen Yeh
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28377500/innate-immune-signaling-in-drosophila-is-regulated-by-tgf%C3%AE-activated-kinase-tak1-triggered-ubiquitin-editing
#6
Li Chen, Nicholas Paquette, Shahan Mamoor, Florentina Rus, Anubhab Nandy, John Leszyk, Scott A Shaffer, Neal Silverman
Coordinated regulation of innate immune responses is necessary in all metazoans. In Drosophila, the Imd pathway detects gram-negative bacterial infections through recognition of DAP-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide (AMP) gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and K63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear...
April 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28370157/an-exploratory-clinical-trial-of-bortezomib-in-patients-with-lower-risk-myelodysplastic-syndromes
#7
May Daher, Juliana Elisa Hidalgo Lopez, Jasleen K Randhawa, Kausar Jabeen Jabbar, Yue Wei, Naveen Pemmaraju, Gautam Borthakur, Tapan Kadia, Marina Konopleva, Hagop M Kantarjian, Katherine Hearn, Zeev Estrov, Steven Reyes, Carlos E Bueso-Ramos, Guillermo Garcia-Manero
Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow...
March 31, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28367085/functional-analysis-of-a-nonsyndromic-hearing-loss-associated-mutation-in-the-transmembrane-ii-domain-of-the-gjc3-gene
#8
Swee-Hee Wong, Wen-Hung Wang, Pin-Hua Chen, Shuan-Yow Li, Jiann-Jou Yang
In a previous study, we identified a novel missense mutation, p.W77S, in the GJC3 gene encoding connexin30.2/connexin31.3 (CX30.2/CX31.3) from patients with hearing loss. The functional alteration of CX30.2/CX31.3 caused by the p.W77S mutant of GJC3 gene, however, remains unclear. In the current study, our result indicated that the p.W77 is localized at the second membrane-spanning segments (TM2) and near border of the E1 domain of the CX30.2/CX31.3 protein and highly conserved (Conseq score = 8~9) in all species...
2017: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/28306745/nickel-and-cadmium-induced-slbp-depletion-a-potential-pathway-to-metal-mediated-cellular-transformation
#9
Ashley Jordan, Xiaoru Zhang, Jinquan Li, Freda Laulicht-Glick, Hong Sun, Max Costa
Both nickel and cadmium compounds have been established as group I carcinogens for several decades. Despite over-whelming evidence of these compounds' carcinogenicity in humans, the specific underlying molecular mechanisms that govern metal induced cellular transformation remain unclear. In this study, we found that there were slightly different effects on decreased SLBP mRNA and protein as well as increased polyA H3.1 in our nickel exposed cells. This suggested that nickel and arsenic have similar effects on canonical histone mRNA transcription and translation...
2017: PloS One
https://www.readbyqxmd.com/read/28107546/bone-marrow-stroma-protects-myeloma-cells-from-cytotoxic-damage-via-induction-of-the-oncoprotein-muc1
#10
Michal Bar-Natan, Dina Stroopinsky, Katarina Luptakova, Maxwell D Coll, Arie Apel, Hasan Rajabi, Athalia R Pyzer, Kristen Palmer, Michaela R Reagan, Myrna R Nahas, Rebecca Karp Leaf, Salvia Jain, Jon Arnason, Irene M Ghobrial, Kenneth C Anderson, Donald Kufe, Jacalyn Rosenblatt, David Avigan
Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis...
March 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28094456/waldenstr%C3%A3-m-macroglobulinemia-2017-update-on-diagnosis-risk-stratification-and-management
#11
Morie A Gertz
Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients. Risk Stratification: Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis...
February 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28090674/nonstructural-protein-5b-promotes-degradation-of-the-nore1a-tumor-suppressor-to-facilitate-hepatitis-c-virus-replication
#12
Payal Arora, Amartya Basu, M Lee Schmidt, Geoffrey J Clark, Howard Donninger, Daniel B Nichols, Diego F Calvisi, Neerja Kaushik-Basu
Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B...
May 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28074489/a-novel-nf-%C3%AE%C2%BAb-inhibitor-edasalonexent-cat-1004-in-development-as-a-disease-modifying-treatment-for-patients-with-duchenne-muscular-dystrophy-phase-1-safety-pharmacokinetics-and-pharmacodynamics-in-adult-subjects
#13
Joanne M Donovan, Michael Zimmer, Elliot Offman, Toni Grant, Michael Jirousek
In Duchenne muscular dystrophy (DMD), NF-κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF-κB upon intracellular cleavage to these bioactive components...
May 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28069439/hakai-an-e3-ligase-for-e-cadherin-stabilizes-%C3%AE-catenin-through-src-kinase
#14
Hridaya Shrestha, Taeyong Ryu, Young-Woo Seo, So-Yeon Park, Yongfeng He, Weiye Dai, Eunsook Park, Shishli Simkhada, Hangun Kim, Keesook Lee, Kwonseop Kim
Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating development of the epithelial-mesenchymal transition of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates β-catenin-mediated oncogenic signals. Although several published data show the interactions between δ-catenin and E-cadherin and between Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai...
February 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28067322/a-novel-and-conserved-plasmodium-sporozoite-membrane-protein-speld-is-required-for-maturation-of-exo-erythrocytic-forms
#15
Faisal Mohammed Abdul Al-Nihmi, Surendra Kumar Kolli, Segireddy Rameswara Reddy, Babu S Mastan, Jyothi Togiri, Mulaka Maruthi, Roshni Gupta, Puran Singh Sijwali, Satish Mishra, Kota Arun Kumar
Plasmodium sporozoites are the infective forms of malaria parasite to vertebrate host and undergo dramatic changes in their transcriptional repertoire during maturation in mosquito salivary glands. We report here the role of a novel and conserved Plasmodium berghei protein encoded by PBANKA_091090 in maturation of Exo-erythrocytic Forms (EEFs) and designate it as Sporozoite surface Protein Essential for Liver stage Development (PbSPELD). PBANKA_091090 was previously annotated as PB402615.00.0 and its transcript was recovered at maximal frequency in the Serial Analysis of the Gene Expression (SAGE) of Plasmodium berghei salivary gland sporozoites...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28027448/induced-pluripotent-hd-monkey-stem-cells-derived-neural-cells-for-drug-discovery
#16
Tanut Kunkanjanawan, Richard Carter, Kwan-Sung Ahn, Jinjing Yang, Rangsun Parnpai, Anthony W S Chan
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28005959/an-intranasal-proteosome-adjuvanted-trivalent-influenza-vaccine-is-safe-immunogenic-efficacious-in-the-human-viral-influenza-challenge-model-serum-igg-mucosal-iga-are-important-correlates-of-protection-against-illness-associated-with-infection
#17
Rob Lambkin-Williams, Colin Gelder, Richard Broughton, Corey P Mallett, Anthony S Gilbert, Alex Mann, David He, John S Oxford, David Burt
INTRODUCTION: A Proteosome-adjuvanted trivalent inactivated influenza vaccine (P-TIV) administered intra-nasally was shown to be safe, well tolerated and immunogenic in both systemic and mucosal compartments, and effective at preventing illness associated with evidence of influenza infection. METHODS: In two separate studies using the human viral challenge model, subjects were selected to be immunologically naive to A/Panama/2007/1999 (H3N2) virus and then dosed via nasal spray with one of three regimens of P-TIV or placebo...
2016: PloS One
https://www.readbyqxmd.com/read/27999193/the-novel-anticancer-agent-jnj-26854165-is-active-in-chronic-myeloid-leukemic-cells-with-unmutated-bcr-abl-and-t315i-mutant-bcr-abl-through-promoting-proteosomal-degradation-of-bcr-abl-proteins
#18
Liangshun You, Hui Liu, Jian Huang, Wanzhuo Xie, Jueying Wei, Xiujin Ye, Wenbin Qian
Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27996044/translational-regulation-of-apobec3g-mrna-by-vif-requires-its-5-utr-and-contributes-to-restoring-hiv-1-infectivity
#19
Santiago Guerrero, Camille Libre, Julien Batisse, Gaëlle Mercenne, Delphine Richer, Géraldine Laumond, Thomas Decoville, Christiane Moog, Roland Marquet, Jean-Christophe Paillart
The essential HIV-1 viral infectivity factor (Vif) allows productive infection of non-permissive cells expressing cytidine deaminases APOBEC3G (A3G) and A3F by decreasing their cellular level, and preventing their incorporation into virions. Unlike the Vif-induced degradation of A3G, the functional role of the inhibition of A3G translation by Vif remained unclear. Here, we show that two stem-loop structures within the 5'-untranslated region of A3G mRNA are crucial for translation inhibition by Vif in cells, and most Vif alleles neutralize A3G translation efficiently...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27978429/dapk1-keeps-the-peace-in-antifungal-inflammation
#20
Tonia Akoumianaki, Georgios Chamilos
Unabated inflammation and impaired antifungal immunity underlie genetic defects in NOX-2-dependent activation of LC3-associated phagocytosis (LAP). In this issue of Cell Host & Microbe, Oikonomou et al. (2016) identify a molecular link between IFN-γ/DAPK1 signaling, the proteosomal degradation pathway, and LAP that is critical for dampening Aspergillus-triggered immunopathology.
December 14, 2016: Cell Host & Microbe
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