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Leonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, Manuela Quintavalle
Adult vascular smooth muscle cells (VSMCs) possess the peculiar ability to de-differentiate in response to extracellular cues, such as vascular damage and inflammation. De-differentiated VSMCs are proliferative, migratory, and have decreased contractile capacity. VSMC dedifferentiation contributes not only to vascular repair, but also to cardiovascular pathologies, such as intimal hyperplasia/restenosis in coronary artery or peripheral vascular diseases and arterial aneurysm. We here demonstrate the role of ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity...
March 20, 2018: Journal of Clinical Investigation
Karin Kosulin, Elena Lam, Albert Heim, Thomas Dobner, Estefanía Rodríguez
BACKGROUND: Human adenoviral (HAdV) infections are usually mild and self-limited, however, some infections from species A, B, C, D and E, can cause severe illnesses, which have raised public health concerns over the past few years. Current available antiviral therapies have limited efficacy and severe toxicity; therefore, finding new targets for specific anti-adenoviral drug design is urgently needed. Our previous work showed that the small molecule compound, HBX, inhibits HAdV type 5 (species C, HAdV-C5) replication and oncogenic transformation through inhibition of the cellular pro-viral factor ubiquitin-specific protease 7 (USP7)...
March 20, 2018: Antiviral Therapy
Korbinian N Kropp, Stefanie Maurer, Kathrin Rothfelder, Bastian J Schmied, Kim L Clar, Moritz Schmidt, Benedikt Strunz, Hans-Georg Kopp, Alexander Steinle, Frank Grünebach, Susanne M Rittig, Helmut R Salih, Daniela Dörfel
The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin-proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses...
March 19, 2018: Cancer Immunology, Immunotherapy: CII
Yan Sun, Yong-Hao Huang, Feng-Ying Huang, Wen-Li Mei, Quan Liu, Cai-Chun Wang, Ying-Ying Lin, Canhua Huang, Yue-Nan Li, Hao-Fu Dai, Guang-Hong Tan
Rationale: Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells. Methods: Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry...
2018: Theranostics
Zhiyuan Xing, Fengbo Sun, Wang He, Zhiwei Wang, Xiuqi Song, Fengjuan Zhang
Ubiquitin-specific peptidase 39 (USP39) has been reported to participate in the mitotic spindle checkpoint and the process of cytokinesis. and has been identified as a therapeutic target for various types of cancer. However, the effect of USP39 in colorectal cancer (CRC) has not been investigated. To explore the functional role of USP39 in CRC cell growth, lentivirus-mediated RNA interference was applied to inhibit USP39 expression in SW1116 and HCT116 cells. The relative USP39 mRNA and protein expression levels were significantly reduced in the USP39 knockdown cells, as verified by reverse transcription-quantitative polymerase chain reaction and western blot analysis...
April 2018: Oncology Letters
Yuyong Tan, Deliang Liu, Jian Gong, Jia Liu, Jirong Huo
F-box only protein 31 (FBXO31), initially identified in 2005, is a novel subunit of the S-phase kinase associated protein 1-Cullin 1-F-box ubiquitin ligase. As with other F-box proteins, FBXO31 may interact with several proteins to promote their ubquitination and subsequent degradation in an F-box-dependent manner. It has been revealed that FBXO31 serves a crucial role in DNA damage response and tumorigenesis. However, the expression and function of FBXO31 varies in different types of human cancer. To the best of our knowledge, the present review is the first to summarize the role of FBXO31 in different types of human cancer and determine its underlying mechanisms, thereby paving the road for the design of FBXO31-targeted anticancer therapies...
April 2018: Oncology Letters
Xia Hou, Hongguang Wei, Carthic Rajagopalan, Hong Jiang, Qingtian Wu, Khalequz Zaman, Youming Xie, Fei Sun
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD...
March 19, 2018: Scientific Reports
Lina Wang, Wenli Feng, Xiao Yang, Feifei Yang, Rong Wang, Qian Ren, Xiaofan Zhu, Guoguang Zheng
The ubiquitin-proteasome system (UPS) participates in both physiological and pathological processes through the posttranslational regulation of intracellular signal transduction pathways. F-box and WD-40 domain protein 11 (Fbxw11) is a component of the SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex. Fbxw11 regulates various signal transduction pathways, and it may have pathological roles in tumorigenesis. However, the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown...
March 19, 2018: Cell Death & Disease
Yingying Zhang, Xulei Zheng, Hao Tan, Yilu Lu, Dachang Tao, Yunqiang Liu, Yongxin Ma
HDAC3 is involved in deacetylation of histone and non-histone proteins, having a key role in the regulation of gene transcription and also in the process of tumorgenesis. However, how HDAC3 is regulated in cancer remains largely unclear. Here, we showed that PIWIL2 can interact with HDAC3, leading to stabilization of HDAC3 from ubiquitin-mediated degradation by competitive association with E3 ubiquitin ligase Siah2. Furthermore, we found that expression of PIWIL2 enhanced HDAC3 activity via CK2α. PIWIL2 facilitated the interaction between HDAC3 and CK2α, thus exhibiting a promotion on the HDAC3 phosphorylation by CK2α...
March 19, 2018: Cell Death & Disease
Junli Liu, Xinfang Huang, Shumeng Hao, Yan Wang, Manman Liu, Jing Xu, Xingli Zhang, Tao Yu, Shucheng Gan, Dongfang Dai, Xuan Luo, Qingyan Lu, Chaoming Mao, Yanyun Zhang, Nan Shen, Bin Li, Mingzhu Huang, Xiaodong Zhu, Jin Jin, Xuhong Cheng, Shao-Cong Sun, Yichuan Xiao
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Although the functional importance of plasma cells and autoantibodies in SLE has been well established, the underlying molecular mechanisms of controlling autoantibody production remain poorly understood. Here we show that Peli1 has a B cell-intrinsic function to protect against lupus-like autoimmunity in mice. Peli1 deficiency in B cells induces autoantibody production via noncanonical NF-κB signaling...
March 19, 2018: Nature Communications
Hee Kyoung Chung, Shelley R Wang, Lan Xiao, Navneeta Rathor, Douglas J Turner, Peixin Yang, Myriam Gorospe, Jaladanki N Rao, Jian-Ying Wang
The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis depends on a dynamic balance among proliferation, migration, apoptosis, and differentiation of intestinal epithelial cells (IECs). The PP2A-associated protein α4 controls the activity and specificity of serine/threonine phosphatases and is thus implicated in many cellular processes. Here we investigated the mechanisms whereby α4 controls the homeostasis of the intestinal epithelium using a genetic approach...
March 19, 2018: Molecular and Cellular Biology
Lu Wang, Jian Kang, Liangzhong Lim, Yuanyuan Wei, Jianxing Song
TDP-43 inclusions are characterized by a large spectrum of neurodegenerative diseases such as ALS and Alzheimer's. Functionally, TDP-43 is engaged in forming dynamic granules via liquid-liquid phase separation (LLPS), which is now recognized to be a general principle for organizing a variety of cellular membrane-less organelles. TDP-43 is composed of the N-terminal domain (NTD) adopting an ubiquitin-like fold, two RRMs and C-terminal domain (CTD) with the low-complexity (LC) prion-like sequences. Previously, only the CTD was found to undergo LLPS to form dynamic liquid droplets with relatively small numbers and sizes...
March 16, 2018: Biochemical and Biophysical Research Communications
Beverly Pappas, Yujie Yang, Yu Wang, Kyung Kim, Hee Jae Chung, Michael Cheung, Katie Ngo, Annie Shinn, William K Chan
The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which involves in diverse biological functions ranging from cancer metastasis to immune regulation. This receptor forms a cytoplasmic complex with Hsp90, p23, and XAP2. We have previously reported that down-regulation of p23 triggers degradation of the AHR protein, uncovering a potentially dynamic event which controls the cellular AHR levels without ligand treatment. Here we investigate the underlying mechanisms for this p23 effect using wild-type HeLa and the p23 knockdown HeLa cells...
March 16, 2018: Biochemical Pharmacology
Wasim Khan, Brian T Layden, Partha Chakrabarti
Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial energy metabolism and modulates activity of mammalian/mechanistic target of rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for certain types of cancer but with limited success. Since glutamine is essential for growth of many cancers, we reasoned that glutamine deprivation under conditions of mTOR inhibition should be more detrimental to cancer cell survival. However, our results show that when cells are deprived of glutamine concomitant with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which aids in their survival due to enhanced autophagic flux...
March 16, 2018: Biochimica et Biophysica Acta
Ming Hu, Zhenhui Zhang, Bin Liu, Shuangwei Zhang, Renjie Chai, Xiaohua Chen, Tianyu Kong, Fangcheng Zhang, Jingzhi Zhang, Shiming Liu, Ningning Liu
BACKGROUND/AIMS: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood...
March 15, 2018: Cellular Physiology and Biochemistry
Myeongsang Lee, Hyunsung Choi, Gwonchan Yoon, Sungsoo Na
Experimental force spectroscopy has been effectively utilized for measuring structural characterization of biomolecules and mechanical properties of biomaterials. Specifically, atomic force microscopy (AFM) has been widely used to portray biomolecular characterization in single-molecule experiment by observing the unfolding behavior of the proteins. Not only the experimental techniques enable us to characterize globular protein, but computational methods like molecular dynamics (MD) also gives insight into understanding biomolecular structures...
March 12, 2018: Journal of Molecular Graphics & Modelling
Konstantinos Feidantsis, Hans O Pörtner, Elisavet Vlachonikola, Efthimia Antonopoulou, Basile Michaelidis
Seasonal temperature changes may take organisms to the upper and lower limit of their thermal range, with respective variations in their biochemical and metabolic profile. To elucidate these traits, we investigated metabolic and antioxidant patterns in tissues of sea bream Sparus aurata during seasonal acclimatization for 1 yr in the field. Metabolic patterns were assessed by determining lactate dehydrogenase, citrate synthase, and β-hydroxyacyl CoA dehydrogenase activities, their kinetic properties and plasma levels of glucose, lactate, and triglycerides and tissue succinate levels...
May 2018: Physiological and Biochemical Zoology: PBZ
Chao Shi, Bei-Qing Pan, Feng Shi, Zhi-Hui Xie, Yan-Yi Jiang, Li Shang, Yu Zhang, Xin Xu, Yan Cai, Jia-Jie Hao, Ming-Rong Wang
Esophageal squamous cell carcinoma (ESCC) is one of the malignancies in digestive system, with a low 5-year survival rate. We previously revealed that Sequestosome 1 (SQSTM1/p62) protein levels were upregulated in ESCC tissues. However, it is unclear about the function of p62 and the underlying mechanism. Here, we used immunofluorescence and immunohistochemistry to investigate the expression of p62 in ESCC. Western blotting, quantitative RT-PCR, colony formation assay, flow cytometry, immunoprecipitation and xenograft tumor assay were used to analyze the role of p62 in vitro and vivo...
March 19, 2018: Oncogene
Meenakshi Ravichandran, Steffen Priebe, Giovanna Grigolon, Leonid Rozanov, Marco Groth, Beate Laube, Reinhard Guthke, Matthias Platzer, Kim Zarse, Michael Ristow
Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins...
March 3, 2018: Cell Metabolism
Qin Chen, Rong Deng, Xian Zhao, Haihua Yuan, Hailong Zhang, Jinzhuo Dou, Ran Chen, Hui Jin, Yanli Wang, Jian Huang, Jianxiu Yu
BACKGROUND/AIMS: An increasing number of studies have linked <unterline>e</unterline>rythropoietin-<unterline>p</unterline>roducing <unterline>h</unterline>epatocellular carcinoma (Eph) family receptor tyrosine kinases to cancer progression. However, little knowledge is available about the regulation of their functions in cancer. METHODS: SUMOylation was analyzed by performing Ni2+-NTA pull-down assay and immunoprecipitation. Cell proliferation, anchorage-independent growth, and tumorigenesis in vivo were examined by cell counting kit-8, soft agar colony formation assay, and a xenograft tumor mouse model, respectively...
March 13, 2018: Cellular Physiology and Biochemistry
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