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Tsai-Mu Cheng, Yu-Tang Chin, Yih Ho, Yi-Ru Chen, Yung-Ning Yang, Yu-Chen Yang, Ya-Jang Shih, Ting-I Lin, Hung-Yun Lin, Paul J Davis
Cyclooxygenase (COX)-2 has been implicated in cancer development. However, resveratrol-induced nuclear accumulation of COX-2 enhances p53-dependent anti-proliferation in different types of cancers. Treatment with resveratrol leads to phosphorylation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), and accumulation of nuclear COX-2 to complex with pERK1/2 and p53. The consequence is Ser-15 phosphorylation of p53 (pSer15-p53), and induction of anti-proliferation in cancer cells. We investigated the mechanisms by which resveratrol-inducible COX-2 facilitates p53-dependent anti-proliferation in prostate cancer LNCaP cells...
December 11, 2017: Food and Chemical Toxicology
Cong Wang, Nanfang Zeng, Siyu Liu, Qi Miao, Lei Zhou, Xinna Ge, Jun Han, Xin Guo, Hanchun Yang
SUMOylation is a reversible post-translational modification that regulates the function of target protein. In this study, we first predicted by software that the multiple proteins of porcine reproductive and respiratory syndrome virus (PRRSV) could be sumoylated. Next, we confirmed that Nsp1β, Nsp4, Nsp9, Nsp10 and nucleocapsid (N) protein of PRRSV could interact with the sole SUMO E2 conjugating enzyme Ubc9, and Ubc9 could be co-localized with Nsp1β, Nsp4, Nsp9 and Nsp10 in the cytoplasm, while with N protein in both the cytoplasm and nucleus...
2017: PloS One
Maki Komiya, Akihiro Ito, Mizuki Endo, Daisuke Hiruma, Mitsuru Hattori, Hisato Saitoh, Minoru Yoshida, Takeaki Ozawa
Post-translational modification by the Small Ubiquitin-related Modifier (SUMO) is indispensable for diverse biological mechanisms. Although various attempts have been made to discover novel SUMO substrate proteins to unveil the roles of SUMOylation, the reversibility of SUMOylation, and the differences in the SUMOylation level still makes it difficult to explore infrequently-SUMOylated proteins in mammalian cells. Here, we developed a method to screen for mammalian SUMOylated proteins using the reconstitution of split fluorescent protein fragments in living mammalian cells...
December 12, 2017: Scientific Reports
Mandar T Naik, Mooseok Kang, Chun-Chen Ho, Pei-Hsin Liao, Yung-Lin Hsieh, Nandita M Naik, Szu-Huan Wang, Iksoo Chang, Hsiu-Ming Shih, Tai-Huang Huang
The negatively charged amino acid-dependent sumoylation motif (NDSM) carries an additional stretch of acidic residues downstream of the consensus Ψ-K-x-E/D sumoylation motif. We have previously shown that acetylation of the SUMO E2 conjugase enzyme, Ubc9, at K65 downregulates its binding to the NDSM and renders a selective decrease in sumoylation of substrates with the NDSM motif. Here, we provide detailed structural, thermodynamic, and kinetics results of the interactions between Ubc9 and its K65 acetylated variant (Ac-Ubc9K65) with three NDSMs derived from Elk1, CBP, and Calpain2 to rationalize the mechanism beneath this reduced binding...
December 12, 2017: Scientific Reports
Ramesh Kumar, Cheok Chit Fang
RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci...
December 12, 2017: Scientific Reports
Pierre Lapaquette, Sabrina Fritah, Nouara Lhocine, Alexandra Andrieux, Giulia Nigro, Joëlle Mounier, Philippe Sansonetti, Anne Dejean
Disruption of the sumoylation/desumoylation equilibrium is associated with several disease states such as cancer and infections, however the mechanisms regulating the global SUMO balance remain poorly defined. Here, we show that infection by Shigella flexneri, the causative agent of human bacillary dysentery, switches off host sumoylation during epithelial cell infection in vitro and in vivo and that this effect is mainly mediated by a calcium/calpain-induced cleavage of the SUMO E1 enzyme SAE2, thus leading to sumoylation inhibition...
December 12, 2017: ELife
Shyam Kumar Gudey, Reshma Sundar, Carl-Henrik Heldin, Anders Bergh, Marene Landström
Transforming growth factor β (TGFβ) is a key regulator of epithelial-to-mesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGFβ, on ΕΜΤ, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGFβ stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGFβ receptor I (TβRI) and the transcriptional repressor Hes1...
November 17, 2017: Oncotarget
Manabu Koike, Yasutomo Yutoku, Aki Koike
Molecularly targeted therapies have high specificity and significant cancer-killing effect. However, their antitumor effect might be greatly diminished by variation in even a single amino acid in the target site, as it occurs, for example, as a consequence of SNPs. Increasing evidence suggests that the DNA repair protein Ku80 is an attractive target molecule for the development of next-generation radiosensitizers for human cancers. However, the localization, post-translational modifications (PTMs), and complex formation of Ku80 have not been elucidated in canines...
December 2017: FEBS Open Bio
Piotr Bialik, Katarzyna Woźniak
Sumoylation is one of the post-translational modifications of proteins, responsible for the regulation of many cellular processes, such as DNA replication and repair, transcription, signal transduction and nuclear transport. During sumoylation, SUMO proteins are covalently attached to the ε-amino group of lysine in target proteins via an enzymatic cascade that requires the sequential action of E1, E2 and E3 enzymes. An important aspect of sumoylation is its reversibility, which involves SUMO-specific proteases called SENPs...
December 8, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
Dianhui Xiu, Zongqiang Wang, Lu Cui, Jinlan Jiang, Haishan Yang, Guifeng Liu
Oxidative stress-induced mitochondrial function and cell apoptosis to osteoblasts, plays a critical role in the pathophysiology of osteoporosis. However, mechanisms underlying such process remain not yet clear. We aims in this study to investigate a possible role of SMAD (the mothers against decapentaplegic homolog 4 (SMAD4) in the oxidative stress-induced apoptosis, in homo sapiens osteoblast hFOB1.19 cells. Results demonstrated that the treatment with more than 100μM H2O2 significantly downregulated the cellular viability, whereas markedly induced apoptosis in hFOB1...
December 5, 2017: Cytokine
Erin Knock, Shinsuke Matsuzaki, Hironori Takamura, Kanayo Satoh, Grace Rooke, Kyung Han, Hong Zhang, Agnieszka Staniszewski, Taiichi Katayama, Ottavio Arancio, Paul E Fraser
Small ubiquitin-related modifiers (SUMOs) conjugated or bound to target proteins can affect protein trafficking, processing and solubility. SUMOylation has been suggested to play a role in the amyloid plaque and neurofibrillary tangle pathology of Alzheimer disease (AD) and related neurodegenerative diseases. The current study examines the impact of SUMO1 on processing of the amyloid precursor protein (APP) leading to the production and deposition of the amyloid-β (Aβ) peptide. An in vivo model of these pathways was developed by the generation of double transgenic mice over-expressing human SUMO1 and a mutant APP...
December 4, 2017: Neurobiology of Disease
Ruihua Wang, Shengfeng Huang, Xianan Fu, Guangrui Huang, Xinyu Yan, Zirui Yue, Shangwu Chen, Yingqiu Li, Anlong Xu
In vertebrates, PIAS genes encode versatile cellular regulators, with functions extremely complex and redundant. Here we try to understand their functions from an evolutionary perspective. we evaluate the sequences, expression and molecular functions of amphioxus PIAS genes and compare them with their vertebrate counterparts. Phylogenetic analysis suggests a single PIAS gene in ancestral chordates, which has been duplicated into four families (PIAS1-4) in vertebrates by 2R-WGD but remained single in a basal chordate (amphioxus)...
December 6, 2017: Scientific Reports
Erbao Zhan, Huapeng Zhou, Sha Li, Lei Liu, Tinghong Tan, Honghui Lin
The conjugation of SUMO (small ubiquitin-like modifier) to protein substrates is a reversible process (SUMOylation/deSUMOylation) that regulates plant development and stress responses. The essential metal copper (Cu) is required for normal plant growth, but excess amounts are toxic. The SUMO E3 ligase SIZ1 and SIZ1-mediated SUMOylation function in plant tolerance to excess Cu. It is unknown whether deSUMOylation also contributes to Cu tolerance in plants. Here we report that OTS1, a protease that cleaves SUMO from its substrate proteins, participates in Cu tolerance in Arabidopsis thaliana (Arabidopsis)...
December 4, 2017: Journal of Integrative Plant Biology
Florian Paasch, Fabian den Brave, Ivan Psakhye, Boris Pfander, Stefan Jentsch
Modification by the ubiquitin-like protein SUMO affects hundreds of cellular substrate proteins and regulates a wide variety of physiological processes. While the SUMO system appears to predominantly target nuclear proteins and, to a lesser extent, cytosolic proteins, hardly anything is known about the SUMOylation of proteins targeted to membrane-enclosed organelles. Here, we identify a large set of structurally and functionally unrelated mitochondrial proteins as substrates of the SUMO pathway in yeast. We show that SUMO modification of mitochondrial proteins does not rely on mitochondrial targeting and, in fact, is strongly enhanced upon import failure, consistent with the modification occurring in the cytosol...
November 28, 2017: Journal of Biological Chemistry
Wei L Hsu, Yun L Ma, Yen C Liu, Eminy H Y Lee
BACKGROUND: Smad4 is a critical effector of TGF-β signaling that regulates a variety of cellular functions. However, its role in the brain has rarely been studied. Here, we examined the molecular mechanisms underlying the post-translational regulation of Smad4 function by SUMOylation, and its role in spatial memory formation. RESULTS: In the hippocampus, Smad4 is SUMOylated by the E3 ligase PIAS1 at Lys-113 and Lys-159. Both spatial training and NMDA injection enhanced Smad4 SUMOylation...
November 28, 2017: BMC Biology
Ramesh Kumar, Román González-Prieto, Zhenyu Xiao, Matty Verlaan-de Vries, Alfred C O Vertegaal
SUMO-targeted ubiquitin ligases (STUbLs) mediate the ubiquitylation of SUMOylated proteins to modulate their functions. In search of direct targets for the STUbL RNF4, we have developed TULIP (targets for ubiquitin ligases identified by proteomics) to covalently trap targets for ubiquitin E3 ligases. TULIP methodology could be widely employed to delineate E3 substrate wiring. Here we report that the single SUMO E2 Ubc9 and the SUMO E3 ligases PIAS1, PIAS2, PIAS3, ZNF451, and NSMCE2 are direct RNF4 targets. We confirm PIAS1 as a key RNF4 substrate...
November 27, 2017: Nature Communications
Ruth Rott, Raymonde Szargel, Vered Shani, Haya Hamza, Mor Savyon, Fatimah Abd Elghani, Rina Bandopadhyay, Simone Engelender
α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions...
November 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
Chih-Yang Huang, Chia-Hua Kuo, Pei-Ying Pai, Tsung-Jung Ho, Yueh-Min Lin, Ray-Jade Chen, Fuu-Jen Tsai, V Vijaya Padma, Wei-Wen Kuo, Chih-Yang Huang
Cardiac hypertrophy is a major characteristic of early-stage hypertension-related heart failure. We have found that the insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II-induced cardiomyocyte hypertrophy and apoptosis. Moreover, this IGF-IIR signaling was elegantly modulated by the heat shock transcription factors (HSFs) during heart failure. However, the detailed mechanism by which HSFs regulates IGF-IIR during hypertension-induced cardiac hypertrophy remains elusive...
November 10, 2017: International Journal of Cardiology
Rebecca A Sager, Mark R Woodford, Len Neckers, Mehdi Mollapour
The molecular chaperone Heat Shock Protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis. The chaperone function of Hsp90 is linked to its ability to bind and hydrolyze ATP. Co-chaperones as well as posttranslational modifications (phosphorylation, SUMOylation, and ubiquitination) are important for its stability and regulation of the ATPase activity. Both mammalian and yeast cells can be used to express and purify Hsp90 and also detect its posttranslational modifications by immunoblotting...
2018: Methods in Molecular Biology
Louise L Hansen, Harrold A van den Burg, Gerben van Ooijen
The transcriptional circadian clock network is tuned into a 24-h oscillator by numerous posttranslational modifications on the proteins encoded by clock genes, differentially influencing their subcellular localization or activity. Clock proteins in any circadian organism are subject to posttranslational regulation, and many of the key enzymes, notably kinases and phosphatases, are functionally conserved between the clocks of mammals, fungi, and plants. We now establish sumoylation, the posttranslational modification of target proteins by the covalent attachment of the small ubiquitin-like modifier protein SUMO, as a novel mechanism regulating key clock properties in the model plant Arabidopsis...
November 1, 2017: Journal of Biological Rhythms
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