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Ran An, Li Cheng, Lijian Chen, Jian Du
Ring finger protein 2 (RNF2), also known as RING2 or RING1B, displays oncogenic functions in different types of cancers, yet, the function of RNF2 during mitosis has not been evaluated. A yeast two‑hybrid screen was undertaken using a human HeLa cDNA library to explore and identify proteins that interact with RNF2. Several positive clones, including Polo‑like kinase 1 (Plk1), a critical regulator of mitosis, were identified. The interaction between RNF2 and Plk1 was confirmed using a β‑galactosidase and growth test in selective media, in vitro glutathione S‑transferase pull‑down, and in vivo immunoprecipitation assays...
May 2018: Oncology Reports
Xun Liu, Yang Zhang, Zhanhong Hu, Qian Li, Lu Yang, Guoqiang Xu
The ubiquitin proteasome system (UPS) plays important roles in the regulation of protein stability, localization, and activity. A myriad of studies have focused on the functions of ubiquitin ligases E3s and deubiquitinating enzymes DUBs due to their specificity in the recognition of downstream substrates. However, the roles of the most ubiquitin-conjugating enzymes E2s are not completely understood except that they transport the activated ubiquitin and form E2-E3 protein complexes. Ubiquitin-conjugating enzyme CDC34 can promote the degradation of downstream targets through the UPS whereas its non-catalytic functions are still elusive...
March 21, 2018: Protein Journal
Guibin Cui, Fengli Sun, Xinmei Gao, Kunliang Xie, Chao Zhang, Shudong Liu, Yajun Xi
Melatonin-mediated osmotic tolerance was attributed to increased antioxidant capacity, energy metabolism, osmoregulation and autophagy in wheat (Triticum aestivum L.). Melatonin is known to play multiple roles in plant abiotic stress tolerance. However, its role in wheat has been rarely investigated. In this study, 25% polyethylene glycol 6000 (PEG 6000) was used to simulate osmotic stress, and wheat seeds and seedlings were treated with different concentrations of melatonin under PEG stress. Isobaric tag for relative and absolute quantification (iTRAQ)-based proteomic techniques were used to identify the differentially accumulated proteins from melatonin-treated and non-treated seedlings...
March 21, 2018: Planta
Ke Yao, Sung-Young Lee, Cong Peng, Do Young Lim, Hiroyuki Yamamoto, Joohyun Ryu, Tae-Gyu Lim, Hanyong Chen, Guoguo Jin, Zhenjiang Zhao, Yaping Han, Wei-Ya Ma, Ann M Bode, Zigang Dong
Inflammation is a complex biological host reaction to tissue damage, infection and trauma. Extensive study of the inflammatory response has led to the identification of several protein kinases that are essential for signaling and could be potential therapeutic targets. The RSK family of kinases has multiple cellular functions. In our study, we found that RSK2 is a mediator for inflammation signaling and interacts with TRAF6. In vitro kinase assay results indicated that RSK2 strongly phosphorylates TRAF6 at serines 46, 47 and 48...
March 22, 2018: Oncogene
David S Hewings, Johanna Heideker, Taylur P Ma, Andrew P AhYoung, Farid El Oualid, Alessia Amore, Gregory T Costakes, Daniel Kirchhofer, Bradley Brasher, Thomas Pillow, Nataliya Popovych, Till Maurer, Carsten Schwerdtfeger, William F Forrest, Kebing Yu, John Flygare, Matthew Bogyo, Ingrid E Wertz
Activity-based probes (ABPs) are widely used to monitor the activity of enzyme families in biological systems. Inferring enzyme activity from probe reactivity requires that the probe reacts with the enzyme at its active site; however, probe-labeling sites are rarely verified. Here we present an enhanced chemoproteomic approach to evaluate the activity and probe reactivity of deubiquitinase enzymes, using bioorthogonally tagged ABPs and a sequential on-bead digestion protocol to enhance the identification of probe-labeling sites...
March 21, 2018: Nature Communications
Junyong Wang, Yan Zeng, Shuai Xu, Jiayun Yang, Wanbing Wang, Bo Zhong, Jinying Ge, Lei Yin, Zhigao Bu, Hong-Bing Shu, Hualan Chen, Cao-Qi Lei, Qiyun Zhu
Nonstructural protein 1 (NS1) of influenza A virus regulates innate immune responses via various mechanisms. We previously showed that a naturally occurring deletion (the EALQR motif) in the NS1 effector domain of an H5N1 swine-origin avian influenza virus impairs the inhibition of type I interferon (IFN) in chicken fibroblasts and attenuates virulence in chickens. Here, we found that the virus bearing this deletion in its NS1 effector domain showed diminished inhibition of IFN-related cytokine expression and attenuated virulence in mice...
March 21, 2018: Journal of Virology
Tram T Nguyen, Eun-Mee Park, Yun-Sook Lim, Soon B Hwang
RAD51-associated protein 1 (RAD51AP1) is a member of the multiprotein complexes postulated to carry out RAD51-mediated homologous recombination and DNA repair in mammalian cells. In the present study, we showed that hepatitis C virus (HCV) NS5A directly bound RAD51AP1 and increased protein level of RAD51AP1 through modulation of the ubiquitin-proteasome pathway. We also demonstrated that RAD51AP1 protein levels were increased in the liver tissues of HCV-infected patients and NS5A transgenic mice. Importantly, NS5A impaired DNA repair by disrupting RAD51/RAD51AP1/UAF1 complex and rendered HCV-infected cells more sensitive to DNA damage...
March 21, 2018: Journal of Virology
Guillermo Senisterra, Hugh Y Zhu, Xiao Luo, Hailong Zhang, Guoliang Xun, Chunliang Lu, Wen Xiao, Taraneh Hajian, Peter Loppnau, Irene Chau, Fengling Li, Abdellah Allali-Hassani, Peter Atadja, Counde Oyang, En Li, Peter J Brown, Cheryl H Arrowsmith, Kehao Zhao, Zhengtian Yu, Masoud Vedadi
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function...
March 1, 2018: SLAS Discovery
Daniel Hormaechea-Agulla, Youngjo Kim, Min Sup Song, Su Jung Song
Intracellular communication via ubiquitin (Ub) signaling impacts all aspects of cell biology and regulates pathways critical to human development and viability; therefore aberrations or defects in Ub signaling can contribute to the pathogenesis of human diseases. Ubiquitination consists of the addition of Ub to a substrate protein via coordinated action of E1-activating, E2-conjugating and E3-ligating enzymes. Approximately 40 E2s have been identified in humans, and most are thought to be involved in Ub transfer; although little information is available regarding the majority of them, emerging evidence has highlighted their importance to human health and disease...
March 20, 2018: Molecules and Cells
Xin Li, Adeline Gadzinsky, Liying Gong, Haijun Tong, Virginie Calderon, Yue Li, Daisuke Kitamura, Ulf Klein, Wallace Y Langdon, Fajian Hou, Yong-Rui Zou, Hua Gu
Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we found that deleting E3 ubiquitin ligases Cbl and Cbl-b (Cbls) in GC B cells resulted in the early exit of high-affinity antigen-specific B cells from the GC reaction and thus impaired clonal expansion. Cbls were highly expressed in GC light zone (LZ) B cells, where they promoted the ubiquitination and degradation of Irf4, a transcription factor facilitating PC fate choice...
March 20, 2018: Immunity
Nesibe Peker, Vinay Donipadi, Mridula Sharma, Craig McFarlane, Ravi Kambadur
Parkinson's Disease is a neurodegenerative disease characterized by tremors, muscle stiffness and muscle weakness. Molecular genetic analysis confirmed that mutations in PARKIN and PINK1 genes, which play major roles in mitochondrial quality control and mitophagy, are frequently associated with Parkinson's Disease. PARKIN is an E3 ubiquitin ligase that translocates to mitochondria during loss of mitochondrial membrane potential to increase mitophagy. Although muscle dysfunction is noted in Parkinson's Disease, little is known about the involvement of PARKIN in the muscle phenotype of Parkinson's Disease...
March 21, 2018: American Journal of Physiology. Cell Physiology
Delphine Masschaele, Joris Wauman, Giel Vandemoortele, Delphine De Sutter, Leentje De Ceuninck, Sven Eyckerman, Jan Tavernier
Ring finger protein 41 (RNF41) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of many proteins including ErbB3 receptors, BRUCE and parkin. Next to this, RNF41 regulates the intracellular trafficking of certain JAK2-associated cytokine receptors by ubiquitinating and suppressing USP8 which in turn destabilizes the ESCRT-0 complex. To further elucidate the function of RNF41 we used different orthogonal approaches to reveal the RNF41 protein complex: Affinity Purification-Mass Spectrometry, BioID and Virotrap...
March 21, 2018: Journal of Proteome Research
Michael Fry
Scientific hypotheses may either predict particular unknown facts or accommodate previously-known data. Although affirmed predictions are intuitively more rewarding than accommodations of established facts, opinions divide whether predictive hypotheses are also epistemically superior to accommodation hypotheses. This paper examines the contribution of predictive hypotheses to discoveries of several bio-molecular systems. Having all the necessary elements of the system known beforehand, an abstract predictive hypothesis of semiconservative mode of DNA replication was successfully affirmed...
March 20, 2018: History and Philosophy of the Life Sciences
Honghong Zhou, Yongshuo Liu, Rui Zhu, Fang Ding, Xiufeng Cao, Dongxin Lin, Zhihua Liu
Snail is a key regulator of epithelial-mesenchymal transition (EMT) and plays an important role in tumor progression and metastasis. Snail is rapidly degraded in the cells and its protein level is critically controlled. Although several E3 ligases regulating Snail degradation have been defined, the deubiquitinases (DUBs) responsible for Snail deubiquitination are less studied. We identified ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) as a DUB that stabilizes Snail through preventing its ubiquitination and proteasomal degradation...
March 21, 2018: Oncogene
Kathrin Kunz, Tanja Piller, Stefan Müller
The ubiquitin-related SUMO system controls many cellular signaling networks. In mammalian cells, three SUMO forms (SUMO1, SUMO2 and SUMO3) act as covalent modifiers of up to thousands of cellular proteins. SUMO conjugation affects cell function mainly by regulating the plasticity of protein networks. Importantly, the modification is reversible and highly dynamic. Cysteine proteases of the sentrin-specific protease (SENP) family reverse SUMO conjugation in mammalian cells. In this Cell Science at a Glance article and the accompanying poster, we will summarize how the six members of the mammalian SENP family orchestrate multifaceted deconjugation events to coordinate cell processes, such as gene expression, the DNA damage response and inflammation...
March 20, 2018: Journal of Cell Science
Christos Gournas, Stelios Gkionis, Mélanie Carquin, Laure Twyffels, Donatienne Tyteca, Bruno André
The eukaryotic plasma membrane is compartmentalized into domains enriched in specific lipids and proteins. However, our understanding of the molecular bases and biological roles of this partitioning remains incomplete. The best-studied domain in yeast is the membrane compartment containing the arginine permease Can1 (MCC) and later found to cluster additional transporters. MCCs correspond to static, furrow-like invaginations of the plasma membrane and associate with subcortical structures named "eisosomes" that include upstream regulators of the target of rapamycin complex 2 (TORC2) in the sensing of sphingolipids and membrane stress...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
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
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