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https://www.readbyqxmd.com/read/29769719/klhl22-activates-amino-acid-dependent-mtorc1-signalling-to-promote-tumorigenesis-and-ageing
#1
Jie Chen, Yuhui Ou, Yanyan Yang, Wen Li, Ye Xu, Yuntao Xie, Ying Liu
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental cues, including amino acids1,2 . Deregulation of mTORC1 has been linked with metabolic diseases, cancer and ageing2-4 . In response to amino acids, mTORC1 is recruited by the Rag GTPases to the lysosome, its site of activation5,6 . The GATOR1 complex, consisting of DEPDC5, NPRL3 and NPRL2, displays GAP activity to inactivate Rag GTPases under amino-acid-deficient conditions 7 ...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29768694/de-novo-variants-in-rhobtb2-an-atypical-rho-gtpase-gene-cause-epileptic-encephalopathy
#2
Hazrat Belal, Mitsuko Nakashima, Hiroshi Matsumoto, Kenji Yokochi, Mariko Taniguchi-Ikeda, Kazushi Aoto, Mohammed Badrul Amin, Azusa Maruyama, Hiroaki Nagase, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Kazumoto Iijima, Shigeaki Nonoyama, Naomichi Matsumoto, Hirotomo Saitsu
By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin/proteasome complex...
May 16, 2018: Human Mutation
https://www.readbyqxmd.com/read/29658272/arsenite-targets-the-ring-finger-domain-of-rbx1-e3-ubiquitin-ligase-to-inhibit-proteasome-mediated-degradation-of-nrf2
#3
Ji Jiang, Lok Ming Tam, Pengcheng Wang, Yinsheng Wang
Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response signaling pathway is a major mechanism for the cellular defense against oxidative stress. Arsenite, a widespread contaminant in drinking water, is known to induce oxidative stress and activate Nrf2-dependent signaling pathway through stabilization of Nrf2 protein by inhibiting its ubiquitination via the Cul3-Rbx1-Keap1 (cullin 3, RING-box 1, and Kelch-like ECH-associated protein 1) E3 ubiquitin ligase and its degradation by the 26S proteasome, though the underlying mechanism remains elusive...
April 16, 2018: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29610475/the-long-tail-of-oncogenic-drivers-in-prostate-cancer
#4
Joshua Armenia, Stephanie A M Wankowicz, David Liu, Jianjiong Gao, Ritika Kundra, Ed Reznik, Walid K Chatila, Debyani Chakravarty, G Celine Han, Ilsa Coleman, Bruce Montgomery, Colin Pritchard, Colm Morrissey, Christopher E Barbieri, Himisha Beltran, Andrea Sboner, Zafeiris Zafeiriou, Susana Miranda, Craig M Bielski, Alexander V Penson, Charlotte Tolonen, Franklin W Huang, Dan Robinson, Yi Mi Wu, Robert Lonigro, Levi A Garraway, Francesca Demichelis, Philip W Kantoff, Mary-Ellen Taplin, Wassim Abida, Barry S Taylor, Howard I Scher, Peter S Nelson, Johann S de Bono, Mark A Rubin, Charles L Sawyers, Arul M Chinnaiyan, Nikolaus Schultz, Eliezer M Van Allen
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway...
April 2, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29604273/ubiquitin-specific-protease-8-deubiquitinates-sec31a-and-decreases-large-copii-carriers-and-collagen-iv-secretion
#5
Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Yuka Madoka, Toshiaki Tanaka, Masayuki Komada
Nascent cargo proteins in the endoplasmic reticulum are transported to the Golgi by COPII carriers. Typical COPII vesicles are 60-70 nm in diameter, and much larger macromolecules, such as procollagen, are transported by atypical large COPII carriers in mammalian cells. The formation of large COPII carriers is enhanced by Cul3 ubiquitin ligase, which mono-ubiquitinates Sec31A, a COPII coat protein. However, the deubiquitinating enzyme for Sec31A was unclear. Here, we show that the deubiquitinating enzyme USP8 interacts with and deubiquitinates Sec31A...
March 28, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29577948/l-arginine-induces-antioxidant-response-to-prevent-oxidative-stress-via-stimulation-of-glutathione-synthesis-and-activation-of-nrf2-pathway
#6
Mingcai Liang, Zhengxuan Wang, Hui Li, Liang Cai, Jianghao Pan, Hongjuan He, Qiong Wu, Yinzhao Tang, Jiapei Ma, Lin Yang
Arginine is a conditionally essential amino acid. To elucidate the influence of l-arginine on the activation of endogenous antioxidant defence, male Wistar rats were orally administered daily with l-arginine at different levels of 25, 50, 100 mg/100 g body weight. After 7 and 14 days feeding, the antioxidative capacities and glutathione (GSH) contents in the plasma and in the liver were uniformly enhanced with the increasing consumption of l-arginine, whereas the oxidative stress was effectively suppressed by l-arginine treatment...
March 22, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29568157/light-regulates-the-rubylation-levels-of-individual-cullin-proteins-in-arabidopsis-thaliana
#7
Matthew J Christians, Aron Rottier, Carly Wiersma
In plants, the small protein related to ubiquitin (RUB) modifies cullin (CUL) proteins in ubiquitin E3 ligases to allow for efficient transfer of ubiquitin to substrate proteins for degradation by the 26S proteasome. At the molecular level, the conjugation of RUB to individual CUL proteins is transient in nature, which aids in the stability of the cullins and adaptor proteins. Many changes in cellular processes occur within the plant upon exposure to light, including well-documented changes in the stability of individual proteins...
2018: Plant Molecular Biology Reporter
https://www.readbyqxmd.com/read/29550478/cullin-3-regulates-adams-mediated-ectodomain-shedding-of-amphiregulin
#8
Hironao Nakayama, Tomohisa Sakaue, Masashi Maekawa, Ayako Fujisaki, Shigeki Higashiyama
A disintegrin and metalloproteinase (ADAM) family are crucial enzymes for ectodomain shedding of multiple substrates and are involved in diverse biologic and pathologic processes. However, the molecular mechanism underlying substrate selectivity of ADAMs is poorly understood. In this study, we observed that disruption of actin polymerization by pharmacological inhibitors, latrunculin A (LatA) and cytochalasin D (CyD), induced ectodomain shedding of epidermal growth factor (EGF) family ligands. Induced shedding activity by LatA or CyD was suppressed by a metalloprotease inhibitor KB-R7785, indicating that ADAMs-mediated shedding is tightly controlled by actin cytoskeleton...
April 30, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29547696/piperidinyl-ureas-chemically-control-defective-in-cullin-neddylation-1-dcn1-mediated-cullin-neddylation
#9
Jared T Hammill, Daniel C Scott, Jaeki Min, Michele C Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, Lei Yang, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit...
April 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29511623/a-novel-mutation-in-exon-9-of-cullin-3-gene-contributes-to-aberrant-splicing-in-pseudohypoaldosteronism-type-ii
#10
Leping Shao, Li Cui, Jingru Lu, Yanhua Lang, Irene Bottillo, Xiangzhong Zhao
Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes ( WNK1 , WNK4 , CUL3, and KLHL3 ) have been identified to be responsible for this disease. Cullin 3 (CUL3) and KLHL3 are subunits of Cullin-RING E3 ubiquitin ligase complexes, and the serine-threonine kinases WNK1 and WNK4 are substrates of this ubiquitin ligase. For CUL3 , all mutations associated with PHAII exclusively lead to exon 9 skipping. In this study, we identified a Chinese PHAII kindred caused by a novel synonymous mutation (c...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29503744/the-role-of-reactive-oxygen-species-in-regulating-t-cell-mediated-immunity-and-disease
#11
REVIEW
Emily L Yarosz, Cheong-Hee Chang
T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies...
February 2018: Immune Network
https://www.readbyqxmd.com/read/29472636/cxcl12-cxcr4-mediated-procollagen-secretion-is-coupled-to-cullin-ring-ubiquitin-ligase-activation
#12
Susan Patalano, José Rodríguez-Nieves, Cory Colaneri, Justin Cotellessa, Diego Almanza, Alisa Zhilin-Roth, Todd Riley, Jill Macoska
Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion...
February 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29407955/discovery-of-a-keap1-dependent-peptide-protac-to-knockdown-tau-by-ubiquitination-proteasome-degradation-pathway
#13
Mengchen Lu, Tian Liu, Qiong Jiao, Jianai Ji, Mengmin Tao, Yijun Liu, Qidong You, Zhengyu Jiang
Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau. Peptide 1 showed strong in vitro binding with Keap1 and Tau...
February 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29361671/mechanisms-and-controversies-in-mutant-cul3-mediated-familial-hyperkalemic-hypertension
#14
Mohammed Zubaerul Ferdaus, James A McCormick
Autosomal dominant mutations in Cullin3 (Cul3) cause the most severe form of Familial Hyperkalemic Hypertension (FHHt). Cul3 mutations cause skipping of exon 9 which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the Cullin-Ring ubiquitin Ligase (CRL) family which mediates ubiquitination and thus degradation of cellular proteins including With-no-lysine [K] kinases (WNKs)...
January 17, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29306329/gene-expression-signature-regulated-by-the-keap1-nrf2-cul3-axis-is-associated-with-a-poor-prognosis-in-head-and-neck-squamous-cell-cancer
#15
Akhileshwar Namani, Md Matiur Rahaman, Ming Chen, Xiuwen Tang
BACKGROUND: NRF2 is the key regulator of oxidative stress in normal cells and aberrant expression of the NRF2 pathway due to genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) axis leads to tumorigenesis and drug resistance in many cancers including head and neck squamous cell cancer (HNSCC). The main goal of this study was to identify specific genes regulated by the KEAP1-NRF2-CUL3 axis in HNSCC patients, to assess the prognostic value of this gene signature in different cohorts, and to reveal potential biomarkers...
January 6, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29160310/cyclin-d-cdk4-kinase-destabilizes-pd-l1-via-cullin-3-spop-to-control-cancer-immune-surveillance
#16
Jinfang Zhang, Xia Bu, Haizhen Wang, Yasheng Zhu, Yan Geng, Naoe Taira Nihira, Yuyong Tan, Yanpeng Ci, Fei Wu, Xiangpeng Dai, Jianping Guo, Yu-Han Huang, Caoqi Fan, Shancheng Ren, Yinghao Sun, Gordon J Freeman, Piotr Sicinski, Wenyi Wei
Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer...
January 4, 2018: Nature
https://www.readbyqxmd.com/read/29127303/comprehensive-genomic-analysis-of-oesophageal-squamous-cell-carcinoma-reveals-clinical-relevance
#17
Peina Du, Peide Huang, Xuanlin Huang, Xiangchun Li, Zhimin Feng, Fengyu Li, Shaoguang Liang, Yongmei Song, Jan Stenvang, Nils Brünner, Huanming Yang, Yunwei Ou, Qiang Gao, Lin Li
Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs)...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038302/cullin-3-and-its-adaptor-protein-ankfy1-determine-the-surface-level-of-integrin-%C3%AE-1-in-endothelial-cells
#18
Masashi Maekawa, Kazufumi Tanigawa, Tomohisa Sakaue, Hiromi Hiyoshi, Eiji Kubota, Takashi Joh, Yuji Watanabe, Tomohiko Taguchi, Shigeki Higashiyama
Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is related to numerous pathophysiological events. We previously reported that a RING ubiquitin ligase complex scaffold protein, cullin-3 (CUL3), and one of its adaptor proteins, BAZF, regulated angiogenesis in the mouse retina by suppressing Notch signaling. However, the degree of inhibition of angiogenesis was made greater by CUL3 depletion than by BAZF depletion, suggesting other roles of CUL3 in angiogenesis besides the regulation of Notch signaling...
November 15, 2017: Biology Open
https://www.readbyqxmd.com/read/29032201/klhl7-promotes-tut1-ubiquitination-associated-with-nucleolar-integrity-implications-for-retinitis-pigmentosa
#19
Jaehyun Kim, Fuminori Tsuruta, Tomomi Okajima, Sarasa Yano, Ban Sato, Tomoki Chiba
Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. Recent studies have revealed that mutations in klhl7 gene cause several disorders, such as retinitis pigmentosa (RP). Although KLHL7 is considered to be crucial for regulating the protein homeostasis, little is known about its biological functions. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. TUT1 is normally localized in nucleolus; however, expression of KLHL7 facilitates a vulnerability of nucleolar integrity, followed by a decrease of TUT1 localization in nucleolus...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28981750/prospect-of-divergent-roles-for-the-cul3-system-in-vascular-endothelial-cell-function-and-angiogenesis
#20
REVIEW
Tomohisa Sakaue, Masashi Maekawa, Hironao Nakayama, Shigeki Higashiyama
Tissue remodelling and regeneration in various pathophysiological conditions (e.g. the processes of development, pregnancy, inflammation, wound healing, tissue regeneration, tumor growth, etc.) require angiogenesis, a dynamically coordinated response to stimuli from the extracellular microenvironment. During angiogenic and angiostatic responses, endothelial cells play a central role in the blood vessel formation and regression. Angiostatic responses, which are evoked by crucial factors such as VEGF and DLL4, have been elucidated...
October 1, 2017: Journal of Biochemistry
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