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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...
March 16, 2018: Journal of Medicinal Chemistry
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
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
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
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 1, 2018: European Journal of Medicinal Chemistry
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
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
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
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
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
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
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
Daniel M Pinkas, Caroline E Sanvitale, Joshua C Bufton, Fiona J Sorrell, Nicolae Solcan, Rod Chalk, James Doutch, Alex N Bullock
Members of the potassium channel tetramerization domain (KCTD) family are soluble non-channel proteins that commonly function as Cullin3 (Cul3)-dependent E3 ligases. Solution studies of the N-terminal BTB domain have suggested that some KCTD family members may tetramerize similarly to the homologous tetramerization domain (T1) of the voltage-gated potassium (Kv) channels. However, available structures of KCTD1, KCTD5 and KCTD9 have demonstrated instead pentameric assemblies. To explore other phylogenetic clades within the KCTD family, we determined the crystal structures of the BTB domains of a further five human KCTD proteins revealing a rich variety of oligomerization architectures, including monomer (SHKBP1), a novel two-fold symmetric tetramer (KCTD10 and KCTD13), open pentamer (KCTD16) and closed pentamer (KCTD17)...
November 1, 2017: Biochemical Journal
Sanneke P M de Boer, Yael Baran, Hector M Garcia-Garcia, Itamar Eskin, Mattie Lenzen, Marcus E Kleber, Evelyn Regar, Peter J de Jaegere, Jurgen M Ligthart, Robert Jan van Geuns, Tehro Lehtimäki, Reijo Laaksonen, Eric Boersma, Winfried März, Erin Halperin, Patrick W Serruys, Wolfgang Koenig
AIMS: The European Collaborative Project on Inflammation and Vascular Wall Remodelling in Atherosclerosis - Intravascular Ultrasound (ATHEROREMO-IVUS) study has been designed as an exploratory clinical study to investigate the associations between genetic variation, coronary atherosclerosis phenotypes, and plaque vulnerability as determined by IVUS. METHODS AND RESULTS: The ATHEROREMO-IVUS study is a prospective, observational study of 581 patients with stable angina pectoris or acute coronary syndrome (ACS) who were referred for coronary angiography to the Thoraxcenter, Rotterdam, enriched with 265 IBIS-2 participants (total population, n=846)...
September 26, 2017: EuroIntervention
Dawei Xu, Hao Zhu, Chengniu Wang, Xinhui Zhu, Genxiang Liu, Chu Chen, Zhiming Cui
Over-production of hydrogen peroxide (H2O2) will lead to human osteoblast dysfunction and apoptosis, causing progression of osteoporosis and osteonecrosis. NF-E2-related factor 2 (Nrf2) is a well-characterized anti-oxidant signaling. Cullin 3 (Cul3) ubiquitin E3 ligase dictates Nrf2 degradation. We demonstrate that microRNA-455 ("miR-455") is a putative Cul3-targeting microRNA. Forced-expression of miR-455 in both hFOB1. 19 osteoblast cell line and primary human osteoblasts induced Cul3 degradation and Nrf2 protein stabilization, which led to subsequent transcription of ARE (anti-oxidant response element)-dependent genes (NQO1, HO1 and GCLC)...
August 29, 2017: Oncotarget
Siqi Wang, Feng Jin, Wenliang Fan, Fang Liu, Yan Zou, Xuehan Hu, Haibo Xu, Ping Han
Diffuse low-grade glioma (DLGG) is a well-differentiated, slow-growing tumour with an inherent tendency to progress to high-grade glioma. The potential roles of genetic alterations in DLGG development have not yet been fully delineated. Therefore, the current study performed an integrated gene expression meta-analysis of eight independent, publicly available microarray datasets including 291 DLGGs and 83 non-glioma (NG) samples to identify gene expression signatures associated with DLGG. Using INMEX, 708 differentially expressed genes (DEGs) (385 upregulated and 323 downregulated genes) were identified in DLGG compared to NG...
September 18, 2017: Scientific Reports
Kyoko Morimoto, Naohiko Ohama, Satoshi Kidokoro, Junya Mizoi, Fuminori Takahashi, Daisuke Todaka, Junro Mogami, Hikaru Sato, Feng Qin, June-Sik Kim, Yoichiro Fukao, Masayuki Fujiwara, Kazuo Shinozaki, Kazuko Yamaguchi-Shinozaki
DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2A (DREB2A) acts as a key transcription factor in both drought and heat stress tolerance in Arabidopsis and induces the expression of many drought- and heat stress-inducible genes. Although DREB2A expression itself is induced by stress, the posttranslational regulation of DREB2A, including protein stabilization, is required for its transcriptional activity. The deletion of a 30-aa central region of DREB2A known as the negative regulatory domain (NRD) transforms DREB2A into a stable and constitutively active form referred to as DREB2A CA...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
Kai Liu, Fang Qin, Xiaolu Sun, Yang Zhang, Jizheng Wang, Yajie Wu, Wenjun Ma, Wei Wang, Xueyi Wu, Ying Qin, Huimin Zhang, Xianliang Zhou, Haiying Wu, Rutai Hui, Yubao Zou, Xiongjing Jiang, Lei Song
BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients...
September 14, 2017: Journal of Hypertension
Fan Xu, Xiao Li, Xu Xiao, Lan-Fang Liu, Li Zhang, Ping-Ping Lin, Sheng-Lin Zhang, Qing-Shan Li
Doxorubicin (DOX) is a widely used anthracycline derivative anticancer drug, but the use of DOX in clinical applications is limited by its cardiotoxicity. In the current research, we were aiming to assess the effects of Ganoderma lucidum polysaccharides (GLPS) on DOX-induced cardiotoxicity and to illustrate the associated mechanisms. H9c2 rat cardiomyocytes were treated with DOX in the absence or presence of GLPS, and we found GLPS treatment ameliorated DOX-induced H9c2 cell death. Moreover, results of in vivo studies indicated that GLPS significantly decreased the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) and attenuated DOX-induced histological changes of the heart tissues...
November 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
De-Chen Lin, Huy Q Dinh, Jian-Jun Xie, Anand Mayakonda, Tiago Chedraoui Silva, Yan-Yi Jiang, Ling-Wen Ding, Jian-Zhong He, Xiu-E Xu, Jia-Jie Hao, Ming-Rong Wang, Chunquan Li, Li-Yan Xu, En-Min Li, Benjamin P Berman, H Phillip Koeffler
OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. DESIGN: Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures...
August 31, 2017: Gut
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