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Áron Szabó, Christian Papin, David Cornu, Elisabeth Chélot, Zoltán Lipinszki, Andor Udvardy, Virginie Redeker, Ugo Mayor, François Rouyer
Circadian clocks have evolved as time-measuring molecular devices to help organisms adapt their physiology to daily changes in light and temperature. Transcriptional oscillations account for a large fraction of rhythmic protein abundance. However, cycling of various posttranslational modifications, such as ubiquitylation, also contributes to shape the rhythmic protein landscape. In this study, we used an in vivo ubiquitin labeling assay to investigate the circadian ubiquitylated proteome of Drosophila melanogaster...
May 22, 2018: Cell Reports
Venkateswara Rao, Bhanu Prakash Petla, Pooja Verma, Prafull Salvi, Nitin Uttam Kamble, Sharboni Ghosh, Harmeet Kaur, Saurabh C Saxena, Manoj Majee
SKP1 (S-Phase Kinase Associated Protein1) proteins are key members of the SCF (SKP-Cullin-F-box protein) E3 ligase complexes that ubiquitinate the target proteins and play diverse roles in plant biology. However, as compared to other members of the SCF complex, study of SKP1-like proteins is very limited in plants. In the present work, we report that Arabidopsis SKP1-like protein13 (ASK13) is differentially regulated in different organs, during seed development and germination, and is upregulated in response to abiotic stresses...
May 18, 2018: Journal of Experimental Botany
Itay Koren, Richard T Timms, Tomasz Kula, Qikai Xu, Mamie Z Li, Stephen J Elledge
Degrons are minimal elements that mediate the interaction of proteins with degradation machineries to promote proteolysis. Despite their central role in proteostasis, the number of known degrons remains small, and a facile technology to characterize them is lacking. Using a strategy combining global protein stability (GPS) profiling with a synthetic human peptidome, we identify thousands of peptides containing degron activity. Employing CRISPR screening, we establish that the stability of many proteins is regulated through degrons located at their C terminus...
May 11, 2018: Cell
Somasundaram Raghavan, Nikhlesh K Singh, Arul M Mani, Gadiparthi N Rao
Although signaling of thrombin via its receptor protease-activated receptor 1 (Par1) is known to occur in atherothrombosis, its link to the actual pathogenesis of this condition is less clear. To better understand the role of thrombin-Par1 signaling in atherosclerosis, here we have studied their effects on cellular cholesterol efflux in mice. We found that by activating Par1 and cullin 3-mediated ubiquitination and degradation of ATP-binding cassette subfamily A member 1 (ABCA1), thrombin inhibits cholesterol efflux in both murine macrophages and smooth muscle cells...
May 18, 2018: Journal of Biological Chemistry
Jia-Shun Zhang, Xue-Jie Li, Lei Yang, Wei-Wei Li, Qun Wang
Studies in E. sinensis have shown that ubiquitination mediated by Cullin-RING E3 ligases (CRLs) plays important roles in spermatogenesis. In other species, CRLs are also essential in cell cycle progression, DNA replication, signal transduction, gene transcription, and development. The catalytic RING component, the RING box protein, is an important part of CRLs. However, there have been few studies on CRLs in crustaceans. In this study, we cloned two RING box protein genes from the Chinese mitten crab, Eriocheir sinensis, termed Es-RBX1 and Es-RBX2 The full length Es-RBX1 cDNA comprises 741 nucleotides, and encodes a protein of 124 amino acid residues, whereas the Es-RBX2 cDNA comprises 1325 nucleotides, and encodes a protein of 110 amino acid residues...
May 15, 2018: Gene
Herman K Edskes, Maryam Mukhamedova, Bouke K Edskes, Reed B Wickner
[URE3] is an amyloid-based prion of Ure2p, a regulator of nitrogen catabolism. While most variants of the [URE3] prion are toxic, mild variants that only slightly slow growth are more widely studied. The existence of several anti-prion systems suggests that some components may be protecting cells from potential detrimental effects of mild [URE3] variants. Our extensive Hermes transposon mutagenesis showed that disruption of YLR352W dramatically slows growth of [URE3-1] strains. Ylr352wp is an F-box protein, directing selection of substrates for ubiquitination by a cullin-containing E-3 ligase...
May 16, 2018: Genetics
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
Maciej Gagat, Adrian Krajewski, Dariusz Grzanka, Alina Grzanka
Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients...
May 16, 2018: Oncology Reports
Jinyan Zhong, Hui Yuan, Xiangqian Xu, Shoufang Kong
MicroRNAs (miRs), a class of small non‑coding RNAs, have been demonstrated to perform promoting or suppressive roles in various types of human malignancy. Deregulation of miR‑195 has been observed in numerous types of human cancer, including cervical cancer; however, the detailed molecular mechanism of miR‑195 underlying the malignant progression of cervical cancer remains largely unclear. In the present study, miR‑195 was significantly downregulated in cervical cancer tissue samples compared with adjacent non‑tumor tissue samples, and the reduced expression level of miR‑195 was associated with node metastasis and an advanced clinical stage in cervical cancer...
May 8, 2018: International Journal of Molecular Medicine
Jing Yang, Min Huang, Liang Zhou, Xian He, Xiaogang Jiang, Yang Zhang, Guoqiang Xu
Chronic inflammation is associated with multiple human disorders such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environment stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its non-enzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process...
May 10, 2018: Journal of Biological Chemistry
Qinxue Li, Wenqiang Wang, Wenlong Wang, Guangqiang Zhang, Yang Liu, Yong Wang, Wei Wang
Adverse environmental conditions, including high temperature, often affect the growth and production of crops worldwide. F-box protein, a core component of the Skp1-Cullin-F-box (SCF) E3 ligase complex, plays an important role in abiotic stress responses. A previously cloned gene from wheat, TaFBA1 , encodes a homologous F-box protein. A Yeast two-Hybrid (Y2H) assay showed that TaFBA1 interacted with other SCF proteins. We found that the expression of TaFBA1 could be induced by heat stress (45°C). Overexpression of TaFBA1 enhanced heat stress tolerance in transgenic tobacco, because growth inhibition was reduced and photosynthesis increased as compared with those in the wild type (WT) plants...
2018: Frontiers in Plant Science
Fei Liu, Li Cao, Ting Zhang, Fen Chang, Yongjie Xu, Qin Li, Jingcheng Deng, Li Li, Genze Shao
The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in diverse biological processes including DNA damage repair and apoptosis. Our previous study has shown that in response to DNA damage HUWE1 was downregulated in CUL4B-mediated ubiquitination and subsequent proteasomal degradation, and CUL4B-mediated regulation of HUWE1 is important for cell survival upon DNA damage. CUL4B is a core component of the CUL4B Ring ligase complexes containing ROC1, DDB1 and a DDB1-Cullin Associated Factors (DCAFs), the latter of which are DDB1-binding WD40 adaptors critical for substrate recognition and recruitment...
May 5, 2018: Biochemical and Biophysical Research Communications
Kai Wang, Xiao Qu, Shaorui Liu, Xudong Yang, Fenglong Bie, Yu Wang, Cuicui Huang, Jiajun Du
PURPOSE: F-box proteins, as components of the Skp1-Cullin 1-F-box protein (SCF) E3 ubiquitin ligase, can specifically bind to substrates and regulate multiple tumor behaviors. However, the role of F-box proteins in squamous-cell lung carcinoma (SqCLC) has not been established. METHODS: We identified the differentially expressed F-box protein-encoding genes in SqCLC by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases...
May 4, 2018: Journal of Cancer Research and Clinical Oncology
Jaewoo Choi, Kyutae Lee, Kristin Ingvarsdottir, Roberto Bonasio, Anita Saraf, Laurence Florens, Michael P Washburn, Saber Tadros, Michael R Green, Luca Busino
Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6...
May 2018: Nature Cell Biology
Peng Li, Jian Xu, Hong-Mei Rao, Xia Li, Yun-Ke Zhang, Fei Jiang, Wen-Xue Wu
MGA_0676 has been characterized as a Mycoplasma gallisepticum nuclease that can induce apoptosis of chicken cells. However, the mechanism by which MGA_0676 induces apoptosis has remained unclear. In this study, we evaluated MGA_0676-induced apoptosis and internalization in immortalized chicken embryo fibroblasts (DF-1) and cancer cell lines. The internalization of MGA_0676 was proven through caveolin-mediated endocytosis by blocking the endocytosis with specific inhibitors or with siRNA. We identified the Thif domain of NEDD8-activating enzyme E1 regulatory subunit (NAE) in DF-1 as the target region interacting with the SNC domain of MGA_0676...
2018: Frontiers in Cellular and Infection Microbiology
Bo Xu, Yuyou Deng, Ran Bi, Haoran Guo, Chang Shu, Neelam Kumari Shah, Junliang Chang, Guanchen Liu, Yujun Du, Wei Wei, Chunxi Wang
PURPOSE: MLN4924 is a second-generation inhibitor that targets ubiquitin-proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo...
April 17, 2018: Cancer Chemotherapy and Pharmacology
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
Marina Stantic, Johanna Wolfsberger, Habib A M Sakil, Margareta T Wilhelm
Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1α in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1α protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1α is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isoform, ∆Np73, increases HIF-1α protein stability...
April 9, 2018: Oncogene
Sallie G De Golia, Consuelo C Cagande, Mary S Ahn, Lisa M Cullins, Art Walaszek, Deborah S Cowley
OBJECTIVE: A Faculty Development Task Force surveyed the American Association of Directors of Psychiatric Residency Training membership to assess faculty development for graduate medical education faculty in psychiatry departments and barriers to seeking graduate medical education careers. METHODS: An anonymous Survey Monkey survey was emailed to 722 American Association of Directors of Psychiatric Residency Training members. The survey included questions about demographics, the current state of faculty development offerings within the respondent's psychiatry department and institution, and potential American Association of Directors of Psychiatric Residency Training faculty development programming...
April 6, 2018: Academic Psychiatry
Sang-Min Jang, Christophe E Redon, Mirit I Aladjem
Cullin-RING (Really Interesting New Gene) E3 ubiquitin ligases (CRLs), the largest family of E3 ubiquitin ligases, are functional multi-subunit complexes including substrate receptors, adaptors, cullin scaffolds, and RING-box proteins. CRLs are responsible for ubiquitination of ~20% of cellular proteins and are involved in diverse biological processes including cell cycle progression, genome stability, and oncogenesis. Not surprisingly, cullins are deregulated in many diseases and instances of cancer. Recent studies have highlighted the importance of CRL-mediated ubiquitination in the regulation of DNA replication/repair, including specific roles in chromatin assembly and disassembly of the replication machinery...
2018: Frontiers in Molecular Biosciences
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