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https://www.readbyqxmd.com/read/28905715/pilot-study-to-assess-the-efficacy-of-ivermectin-and-fenbendazole-for-treating-captive-born-olive-baboons-papio-anubis-coinfected-with-strongyloides-f%C3%A3-lleborni-and-trichuris-trichiura
#1
Mason V Reichard, Jennifer E Thomas, Maria Chavez-Suarez, Cassandra O Cullin, Gary L White, Emily C Wydysh, Roman F Wolf
In this study, we evaluated the efficacy of combined treatment with ivermectin and fenbendazole (IVM-FBZ) for treating captive olive baboons (Papio anubis) infected with Strongyloides fülleborni and Trichuris trichiura, 2 common nematode parasites of these NHP. Infected baboons were treated for a total of 9 wk with ivermectin (400 μg/kg IM twice weekly) and fenbendazole (50 mg/kg PO once daily for 3 d; 3 rounds of treatment, 21 d apart). Five baboons naturally infected with both S. fülleborni and T. trichiura (n = 4) or S...
January 1, 2017: Journal of the American Association for Laboratory Animal Science: JAALAS
https://www.readbyqxmd.com/read/28902348/suppression-of-cul4a-attenuates-tgf-%C3%AE-1-induced-epithelial-to-mesenchymal-transition-in-breast-cancer-cells
#2
Yunshan Wang, Xiaoyan Liu, Hui Zheng, Qin Wang, Li An, Guangwei Wei
Transforming growth factor-β1 (TGF-β1) plays a vital role in the process of epithelial-to-mesenchymal transition (EMT) in breast cancer and the cullin 4A (CUL4A) gene is overexpressed in primary breast cancer. However, whether TGF-β1 signaling can induce CUL4A expression has not been investigated to date, at least to the best of our knowledge. In this study, using breast cancer cell lines, we found that the CUL4A expression level was increased following EMT induced by TGF-β1. Silencing CUL4A expression or CUL4A inhibition by thalidomide suppressed the EMT process induced by TGF-β1...
October 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28898250/effects-of-proteasome-inhibitor-mg-132-on-the-parasite-schistosoma-mansoni
#3
Enyara R Morais, Katia C Oliveira, Renato G de Paula, Alice M M Ornelas, Érika B C Moreira, Fernanda Rafacho Badoco, Lizandra G Magalhães, Sergio Verjovski-Almeida, Vanderlei Rodrigues
Proteasome is a proteolytic complex responsible for intracellular protein turnover in eukaryotes, archaea and in some actinobacteria species. Previous work has demonstrated that in Schistosoma mansoni parasites, the proteasome inhibitor MG-132 affects parasite development. However, the molecular targets affected by MG-132 in S. mansoni are not entirely known. Here, we used expression microarrays to measure the genome-wide changes in gene expression of S. mansoni adult worms exposed in vitro to MG-132, followed by in silico functional analyses of the affected genes using Ingenuity Pathway Analysis (IPA)...
2017: PloS One
https://www.readbyqxmd.com/read/28886238/sirt7-deacetylates-ddb1-and-suppresses-the-activity-of-the-crl4-e3-ligase-complexes
#4
Yan Mo, Ran Lin, Peng Liu, Minjia Tan, Yue Xiong, Kun-Liang Guan, Hai-Xin Yuan
Cullin 4 (CUL4) and small ring finger protein ROC1 assemble to form E3 ubiquitin ligase (CRL4) complexes. CUL4 interacts with WD-40 proteins through the adaptor protein DDB1 to target substrates for ubiquitylation.. Very little is known on how the CUL4 and DDB1 interaction is regulated. Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar SIRT7 as a major deacetylase that negatively regulates DDB1-CUL4 interaction. Following inhibition of nucleolar function by Actinomycin D (ActD) or 5-Fluorouracil (5-FU) treatment or knocking down Pol I component UBF, SIRT7 is mobilized from the nucleolus to the nucleoplasm and promotes DDB1 deacetylation, leading to decreased DDB1-CUL4 association and CRL4 activity...
September 8, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28871425/mir-33a-inhibits-cell-proliferation-and-invasion-by-targeting-cand1-in-lung-cancer
#5
M Kang, Y Li, Y Zhao, S He, J Shi
BACKGROUND: Lung cancer continues to be one of the top five causes of cancer-related mortality. This study aims to identify down- and upregulated miRNAs and mRNA which can be used as potential biomarkers and/or therapeutic targets for lung cancer. METHODS: Integrated analysis of differential expression profiles of miRNA and mRNA in lung cancer was performed by searching Gene Expression Omnibus datasets. Based on miRNA expression profiles, direct mRNA targets of miRNAs with experimental support were identified through miRTarBase...
September 4, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28861005/murine-myocardial-transcriptome-analysis-reveals-a-critical-role-of-cops8-in-the-gene-expression-of-cullin-ring-ligase-substrate-receptors-and-redox-and-vesicle-trafficking-pathways
#6
Ammara Abdullah, Kathleen M Eyster, Travis Bjordahl, Peng Xiao, Erliang Zeng, Xuejun Wang
Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases. Supported primarily by the decrease of substrate receptor (SR) proteins of CRLs in cells deficient of a CSN subunit, CSN-mediated cullin deneddylation is believed to prevent autoubiquitination and self-destruction of the SR in active CRLs...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28851847/rotavirus-nsp1-requires-casein-kinase-ii-mediated-phosphorylation-for-hijacking-of-cullin-ring-ligases
#7
Kaitlin A Davis, Marco Morelli, John T Patton
The rotavirus nonstructural protein NSP1 repurposes cullin-RING E3 ubiquitin ligases (CRLs) to antagonize innate immune responses. By functioning as substrate adaptors of hijacked CRLs, NSP1 causes ubiquitination and proteasomal degradation of host proteins that are essential for expression of interferon (IFN) and IFN-stimulated gene products. The target of most human and porcine rotaviruses is the β-transducin repeat-containing protein (β-TrCP), a regulator of NF-κB activation. β-TrCP recognizes a phosphorylated degron (DSGΦXS) present in the inhibitor of NF-κB (IκB); phosphorylation of the IκB degron is mediated by IκB kinase (IKK)...
August 29, 2017: MBio
https://www.readbyqxmd.com/read/28842501/stress-sensing-mechanisms-and-the-physiological-roles-of-the-keap1-nrf2-system-during-cellular-stress
#8
Takafumi Suzuki, Masayuki Yamamoto
Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses...
August 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28839075/a-pgam5-keap1-nrf2-complex-is-required-for-stress-induced-mitochondrial-retrograde-trafficking
#9
Gary B O'Mealey, Kendra S Plafker, William L Berry, Ralf Janknecht, Jefferson Y Chan, Scott M Plafker
The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition...
August 24, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28838998/the-neddylation-inhibitor-pevonedistat-mln4924-suppresses-and-radiosensitizes-head-and-neck-squamous-carcinoma-cells-and-tumors
#10
Vanessa Vanderdys, Amir Allak, Fadila Guessous, Mouadh Benamar, Paul W Read, Mark J Jameson, Tarek Abbas
The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8 and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC) and its depletion by siRNA inhibits the proliferation of human papilloma virus negative (HPV-ve) HNSCC cells primarily through the induction of rereplication...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28818995/maternal-dcaf2-is-crucial-for-maintenance-of-genome-stability-during-the-first-cell-cycle-in-mice
#11
Yi-Wen Xu, Lan-Rui Cao, Min Wang, Ying Xu, Xin Wu, Junping Liu, Chao Tong, Heng-Yu Fan
Precise regulation of DNA replication and genome integrity is crucial for gametogenesis and early embryogenesis. Cullin ring-finger ubiquitin ligase 4 (CRL4) has multiple functions in the maintenance of germ cell survival, oocyte meiotic maturation, and maternal-zygotic transition in mammals. DDB1-cullin 4-associated factor-2 (DCAF2, also known as DTL or CDT2) is an evolutionarily conserved substrate receptor of CRL4. To determine whether DCAF2 is a key CRL4 substrate adaptor in mammalian oocytes, we generated a novel mouse strain that carries a Dcaf2 allele flanked by LoxP sequences, and specifically deleted Dcaf2 in oocytes...
August 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28818370/overexpression-of-vpeifp1-a-novel-f-box-kelch-repeat-protein-from-wild-chinese-vitis-pseudoreticulata-confers-higher-tolerance-to-powdery-mildew-by-inducing-thioredoxin-z-proteolysis
#12
Jie Wang, Wenkong Yao, Lei Wang, Fuli Ma, Weihuo Tong, Chen Wang, Rui Bao, Changyue Jiang, Yazhou Yang, Jianxia Zhang, Yan Xu, Xiping Wang, Chaohong Zhang, Yuejin Wang
An F-box protein (VpEIFP1) induced by Erysiphe necator was isolated from Vitis pseudoreticulata, a wild Chinese grapevine species naturally resistant to powdery mildew (PM). It contains an F-box domain and two Kelch-repeat motifs. Expression profiles indicate the VpEIFP1 is strongly induced at both transcriptional and translational levels by PM infection. A subcellular localisation assay showed that VpEIFP1 is predominantly located in the nucleus and cytoplasm. Overexpression of VpEIFP1 accelerated the accumulation of hydrogen peroxide (H2O2) and up-regulated the expressions of ICS2, NPR1 and PR1 involved in defence responses, resulting in suppression of PM germination and growth...
October 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28808481/cul4b-is-a-novel-prognostic-marker-in-cholangiocarcinoma
#13
Pengyu Li, Lili Zhang, Muyi Yang, Mei Qi, Xing Jin, Bo Han
Cullin 4B (Cul4B), a scaffold protein that assembles the ubiquitin ligase complex, is involved in a wide variety of physiological and developmental processes, such as cell cycle progression, DNA damage response and gene expression regulation. Cul4B is overexpressed in various solid tumors. However, the prognostic value and role of Cul4B in cholangiocarcinoma (CCA) is largely unknown. The present study demonstrated that Cul4B was overexpressed in 21 (26.6%) of 79 patients with intrahepatic CCA, and in 40 (28...
August 2017: Oncology Letters
https://www.readbyqxmd.com/read/28806398/lysine-52-stabilizes-the-myc-oncoprotein-through-an-scf-fbxw7-independent-mechanism
#14
J De Melo, S S Kim, C Lourenco, L Z Penn
The oncogenic transcription factor c-MYC (MYC) is deregulated and often overexpressed in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would markedly impact patient outcome. MYC is highly regulated, with a protein and mRNA half-life of ~30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCF(Fbxw7)...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#15
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28804198/association-between-cullin-3-single-nucleotide-polymorphism-rs17479770-and-essential-hypertension-in-the-male-chinese-han-population
#16
Jin Li, Jing Hu, Rong Sun, Yongpan Zhao, Heping Liu, Jian Li, Lei Shi, Shujin Zhao
BACKGROUND: Hypertension, including essential and secondary hypertension, is a multifactorial disease, affecting more than one billion people worldwide. Secondary hypertension can result from mutations of cullin-3 (CUL3); however, whether polymorphisms of CUL3 are associated with essential hypertension (EH) has not been reported. Here, we investigated the association between CUL3 SNPs rs17479770 and rs3738952 and EH in the Chinese Han population. METHODS: This case-control study investigated 520 representatives, including 259 patients with EH and 261 normotensive controls matched for age, gender, BMI, TG, TC, and HbA1c for the distribution of functional rs17479770 and rs3738952 within the CUL3 gene by using PCR and RFLP...
2017: Disease Markers
https://www.readbyqxmd.com/read/28802844/structural-basis-for-cullins-and-ring-component-inhibition-targeting-e3-ubiquitin-pathway-conductors-for-cancer-therapeutics
#17
Shagufta Shafique, Waqar Ali, Sonia Kanwal, Sajid Rashid
Cullin (CUL)-RING E3 ubiquitin ligases (CRLs) are attractive therapeutic targets as they regulate diverse biological processes important for cancer cell survival by conferring substrate selectivity for ubiquitination and degradation. Given the complexity of CRL complexes, steps toward the structure-based design of small-molecule inhibitors to modulate their activity have remained elusive. In this study, we explored the structural assembly and interaction details of closely related CUL scaffolds (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7) with RBX1 to screen potent small molecules against CRLs...
August 10, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28776949/structure-guided-design-of-peptides-as-tools-to-probe-the-protein-protein-interaction-between-cullin-2-and-elongin-bc-substrate-adaptor-in-cullin-ring-e3-ubiquitin-ligases
#18
Teresa Cardote, Alessio Ciulli
Cullin RING E3 ubiquitin ligases (CRLs) are large dynamic multi-subunit complexes that control the fate of many proteins in cells. CRLs constitute attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. Here we describe a structure-guided biophysical approach to probe the protein-protein interaction (PPI) between the Cullin-2 scaffold protein and the adaptor subunits Elongin BC within the context of the von Hippel-Lindau complex (CRL2VHL) using peptides...
August 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28717191/mln4924-pevonedistat-a-protein-neddylation-inhibitor-suppresses-proliferation-and-migration-of-human-clear-cell-renal-cell-carcinoma
#19
Shuai Tong, Yang Si, Hefen Yu, Lingqiang Zhang, Ping Xie, Wenguo Jiang
Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC)...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28715492/small-molecule-perturbation-of-the-cand1-cullin1-ubiquitin-cycle-stabilizes-p53-and-triggers-epstein-barr-virus-reactivation
#20
Nadezhda Tikhmyanova, Steve Tutton, Kayla A Martin, Fang Lu, Andrew V Kossenkov, Nicholas Paparoidamis, Shannon Kenney, Joseph M Salvino, Paul M Lieberman
The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates...
July 2017: PLoS Pathogens
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