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#32745599   2020/07/31 To Up

The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation.

Over the last 20 years, a number of studies have provided strong support for protein degradation mediated by the ubiquitin-proteasome system in synaptic plasticity and memory formation. In this system, target substrates become covalently modified by the small protein ubiquitin through a series of enzymatic reactions involving hundreds of different ligases. While some substrates will acquire only a single ubiquitin, most will be marked by multiple ubiquitin modifications, which link together at specific lysine sites or the N-terminal methionine on the previous ubiquitin to form a polyubiquitin chain. There are at least eight known linkage-specific polyubiquitin chains a target protein can acquire, many of which are independent of the proteasome, and these chains can be homogenous, mixed, or branched in nature, all of which result in different functional outcomes and fates for the target substrate. However, as the focus has remained on protein degradation, much remains unknown about the role of these diverse ubiquitin chains in the brain, particularly during activity- and learning-dependent synaptic plasticity. Here, we review the different types and functions of ubiquitin chains and summarize evidence suggesting a role for these diverse ubiquitin modifications in synaptic plasticity and memory formation. We conclude by discussing how technological limitations have limited our ability to identify and elucidate the role of different ubiquitin chains in the brain and speculate on the future directions and implications of understanding linkage-specific ubiquitin modifications in activity- and learning-dependent synaptic plasticity.
Madeline Musaus, Shaghayegh Navabpour, Timothy J Jarome

1835 related Products with: The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation.

100ul4 Membranes/Box96 wells (1 kit)2 Pieces/Box4 Membranes/Box2 Pieces/Box100ug4 Arrays/Slide1 g5mg10 mg

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#32744498   2020/08/03 To Up

Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids.

How cells adjust nutrient transport across their membranes is incompletely understood. Previously, we have shown that broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through endocytosis of sugar- and amino acid transporters (AATs) (Müller et al., 2015). A genome-wide screen now revealed that the selective endocytosis of four AATs during starvation required the α-arrestin family protein Art2/Ecm21, an adaptor for the ubiquitin ligase Rsp5, and its induction through the general amino acid control pathway. Art2 uses a basic patch to recognize C-terminal acidic sorting motifs in AATs and thereby instructs Rsp5 to ubiquitinate proximal lysine residues. When amino acids are in excess, Rsp5 instead uses TORC1-activated Art1 to detect N-terminal acidic sorting motifs within the same AATs, which initiates exclusive substrate-induced endocytosis. Thus, amino acid excess or starvation activate complementary α-arrestin-Rsp5-complexes to control selective endocytosis and adapt nutrient acquisition.
Vasyl Ivashov, Johannes Zimmer, Sinead Schwabl, Jennifer Kahlhofer, Sabine Weys, Ronald Gstir, Thomas Jackschitz, Leopold Kremser, Günther K Bonn, Herbert Lindner, Lukas A Huber, Sebastien Leon, Oliver Schmidt, David Teis

1160 related Products with: Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids.

10 100 UG

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#32744255   2020/07/27 To Up

Structure of the HLTF HIRAN domain and its functional implications in regression of a stalled replication fork.

HLTF (helicase-like transcription factor) is a yeast RAD5 homolog that is found in mammals. HLTF has E3 ubiquitin ligase and DNA helicase activities, and is a pivotal protein in template-switched DNA synthesis that allows DNA replication to continue even in the presence of DNA damage by utilizing a newly synthesized undamaged strand as a template. In addition, HLTF has a DNA-binding domain termed HIRAN (HIP116 and RAD5 N-terminal). HIRAN has been hypothesized to play a role in DNA binding; however, the structural basis of its role in DNA binding has remained unclear. In the past five years, several crystal structures of HIRAN have been reported. These structures revealed new insights into the molecular mechanism underlying DNA binding by HIRAN. Here, the structural information on HIRAN is summarized and the function of HIRAN in recognizing the 3'-terminus of the daughter strand at a stalled replication fork and the implications for its involvement in fork regression are discussed.
Asami Hishiki, Mamoru Sato, Hiroshi Hashimoto

1088 related Products with: Structure of the HLTF HIRAN domain and its functional implications in regression of a stalled replication fork.

100 ug100ug100 ug100 ug100ug100 ug

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#32743553   2020/06/29 To Up

Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells.

Mechanistic understanding of hypoxia-responsive signaling pathways provides important insights into oxygen- and metabolism-dependent cellular phenotypes in diseases. Using SILAC-based quantitative proteomics, we provided a quantitative map identifying over 6300 protein groups in response to hypoxia in prostate cancer cells and identified both canonical and novel cellular networks dynamically regulated under hypoxia. Particularly, we identified SDE2, a DNA stress response modulator, that was significantly downregulated by hypoxia, independent of HIF (hypoxia-inducible factor) transcriptional activity. Mechanistically, hypoxia treatment promoted SDE2 polyubiquitination and degradation. Such regulation is independent of previously identified Arg/N-end rule proteolysis or the ubiquitin E3 ligase, CDT2. Depletion of SDE2 increased cellular sensitivity to DNA damage and inhibited cell proliferation. Interestingly, either SDE2 depletion or hypoxia treatment potentiated DNA damage-induced PCNA (proliferating cell nuclear antigen) monoubiquitination, a key step for translesion DNA synthesis. Furthermore, knockdown of SDE2 desensitized, while overexpression of SDE2 protected the hypoxia-mediated regulation of PCNA monoubiquitination upon DNA damage. Taken together, our quantitative proteomics and biochemical study revealed diverse hypoxia-responsive pathways that strongly associated with prostate cancer tumorigenesis and identified the functional roles of SDE2 and hypoxia in regulating DNA damage-induced PCNA monoubiquitination, suggesting a possible link between hypoxic microenvironment and the activation of error-prone DNA repair pathway in tumor cells.
Ang Luo, Yao Gong, Hyungjin Kim, Yue Chen

2140 related Products with: Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells.



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#32742484   2020/07/11 To Up

MicroRNA-154-5p regulates the HPV16 E7-pRb pathway in Cervical Carcinogenesis by targeting CUL2.

Cervical cancer, induced by persistent HPV infection, has a high mortality rate. The E3 ubiquitin ligase Cullin 2 (CUL2) is critical for HPV16 E7-mediated degradation of retinoblastoma protein (pRb). Dysregulation of microRNAs (miRNAs) is induced during tumorigenesis; however, the association between miRNA networks and CUL2, specific to cervical cancer, remains unknown. Herein, we determined miRNA profiles in cervical cancer tissues using an Affymetrix miRNA array. We found that miR-154-5p was downregulated during cancer progression using real-time quantitative reverse transcription PCR in 130 biopsy specimens. Bioinformatics analysis and dual-luciferase reporter assays indicated that miR-154-5p directly targets the CUL2 3'UTR. To determine the functional consequences of modulating miR-154-5p and CUL2 levels, HPV16-positive cervical cancer cell line (SiHa) was transfected with miR-154-5p mimic, miR-154-5p inhibitor, or CUL2 siRNA. The proliferation, migration, and invasion of transfected cells were evaluated using CCK8 cell counting kit, wound-healing assay, and Transwell invasion assay. Increased miR-154-5p expression promoted significantly reduced SiHa cell proliferation, migration, and invasion, whereas the miR-154-5p inhibitor had the opposite effect. CUL2 silencing had similar effects to those of the miR-154-5p mimic. Consistent with the inverse correlation between miR-154-5p and CUL2 levels, CUL2 silencing also increased pRb expression. To our knowledge, this is the first study to demonstrate that miR-154-5p regulates pRb expression by targeting CUL2 3'UTR, thereby playing a tumor-suppressive role in HPV16 E7-induced cervical carcinogenesis.
Weihong Zhao, Yatao Liu, Lili Zhang, Ling Ding, Yaqin Li, Honglei Zhang, Tong Wang, Min Hao

2533 related Products with: MicroRNA-154-5p regulates the HPV16 E7-pRb pathway in Cervical Carcinogenesis by targeting CUL2.

50 ulInhibitors2 Pieces/Box2 Pieces/Box2 Pieces/Box2 Pieces/Box2 Pieces/Box

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#32742384   2020/06/05 To Up

Construction of a 14-lncRNA risk score system predicting survival of children with acute myelocytic leukemia.

Acute myelocytic leukemia (AML) is a frequent type of acute leukemia. The present study was performed to build a risk score system for the prognostic prediction of AML. AML RNA-sequencing data from samples from 111 children were downloaded from The Cancer Genome Atlas database. Using the DEseq and edgeR packages, the differentially expressed long non-coding RNAs (DE-lncRNAs) between bad and good prognosis groups were identified. A survival package was used to screen prognosis-associated lncRNAs and clinical factors. The optimal lncRNA combination was selected using the penalized package, and the risk-score system was built and evaluated. After the lncRNA-mRNA expression correlation network was constructed, the potential pathways involving the key lncRNAs were enriched using Gene Set Enrichment Analysis. Among the 61 DE-lncRNAs, 48 lncRNAs were significantly associated with prognosis. Relapse was an independent prognostic factor. The optimal 14-lncRNA risk score system was constructed. After 730 differentially expressed mRNAs were identified between the good and bad prognosis groups divided using a prognostic index, the lncRNA-mRNA expression correlation network was constructed. Enrichment analysis showed that semaphorin-3C [SEMA3C; regulated by probable leucine-tRNA ligase, mitochondrial (LARS2-AS1)] and secreted frizzled-related protein 5 [SFRP5; mediated by WASH complex subunit 5 (WASHC5)-antisense RNA 1 (AS1)] were involved in axon guidance and the Wnt signaling pathway, respectively. A 14-lncRNA (including paired box protein Pax8-AS1 and MYB AS1) risk-score system might be effective in predicting the prognosis of AML. Axon guidance (involving SEMA3C and LARS2-AS1) and the Wnt signaling pathway (involving SFRP5 and WASHC5-AS1) might be two important pathways affecting the prognosis of AML.
Shuli Guo, Bo Li, Xiaoyan Xu, Wanli Wang, Songyun Wang, Tao Lv, Huirui Wang

2631 related Products with: Construction of a 14-lncRNA risk score system predicting survival of children with acute myelocytic leukemia.

250 ug 500 Slides 70 Slides 70 Slides

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#32742241   2020/07/21 To Up

Structure-Based Design with Tag-Based Purification and In-Process Biotinylation Enable Streamlined Development of SARS-CoV-2 Spike Molecular Probes.

Biotin-labeled molecular probes, comprising specific regions of the SARS-CoV-2 spike, would be helpful in the isolation and characterization of antibodies targeting this recently emerged pathogen. To develop such probes, we designed constructs incorporating an N-terminal purification tag, a site-specific protease-cleavage site, the probe region of interest, and a C-terminal sequence targeted by biotin ligase. Probe regions included full-length spike ectodomain as well as various subregions, and we also designed mutants to eliminate recognition of the ACE2 receptor. Yields of biotin-labeled probes from transient transfection ranged from ~0.5 mg/L for the complete ectodomain to >5 mg/L for several subregions. Probes were characterized for antigenicity and ACE2 recognition, and the structure of the spike ectodomain probe was determined by cryo-electron microscopy. We also characterized antibody-binding specificities and cell-sorting capabilities of the biotinylated probes. Altogether, structure-based design coupled to efficient purification and biotinylation processes can thus enable streamlined development of SARS-CoV-2 spike-ectodomain probes. Funding: Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID). Support for this work was also provided by COVID-19 Fast Grants, the Jack Ma Foundation, the Self Graduate Fellowship Program, and NIH grants DP5OD023118, R21AI143407, and R21AI144408. Some of this work was performed at the Columbia University Cryo-EM Center at the Zuckerman Institute, and some at the Simons Electron Microscopy Center (SEMC) and National Center for Cryo-EM Access and Training (NCCAT) located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310). Conflict of Interest: The authors declare that they have no conflict of interest. Ethical Approval: Peripheral blood mononuclear cells (PBMCs) for B cell sorting were obtained from a convalescent SARS-CoV-2 patient (collected 75 days post symptom onset under an IRB approved clinical trial protocol, VRC 200 - ClinicalTrials.gov Identifier: NCT00067054) and a healthy control donor from the NIH blood bank pre-SARS-CoV-2 pandemic.
Tongqing Zhou, I-Ting Teng, Adam S Olia, Gabriele Cerutti, Jason Gorman, Alexandra Nazzari, Wei Shi, Yaroslav Tsybovsky, Lingshu Wang, Shuishu Wang, Baoshan Zhang, Yi Zhang, Phinikoula S Katsamba, Yuliya Petrova, Bailey B Banach, Ahmed S Fahad, Lihong Liu, Sheila N Lopez Acevedo, Bharat Madan, Matheus Olivera de Souza, Xiaoli Pan, Pengfei Wang, Jacy R Wolfe, Michael Yin, David D Ho, Emily Phung, Anthony DiPiazza, Lauren Chang, Olubukula Abiona, Kizzmekia S Corbett, Brandon J DeKosky, Barney S Graham, John R Mascola, John Misasi, Tracy Ruckwardt, Nancy J Sullivan, Lawrence Shapiro

1598 related Products with: Structure-Based Design with Tag-Based Purification and In-Process Biotinylation Enable Streamlined Development of SARS-CoV-2 Spike Molecular Probes.

100preparations250mg25ml 100 µgOne 96-Well Microplate KiOne 96-Well Microplate Ki20 ug Product tipe: Antib100 100 200ml25ml One 96-Well Microplate Ki

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#32739834   2020/07/16 To Up

Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain.

Skp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.
Lital Dabool, Ketty Hakim-Mishnaevski, Liza Juravlev, Naama Flint-Brodsly, Silvia Mandel, Estee Kurant

2456 related Products with: Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain.

100 UG 50 UG100 μg1 50 UG1 Set96 tests

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#32739649   2020/07/13 To Up

Discovery of 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives that regulated HPV relevant cellular pathway and prevented cervical cancer from abnormal proliferation.

Human papillomavirus (HPV) is a well-established etiological factor for cervical cancer, and the expression of oncogenic protein E7 is crucial for carcinogenesis. Herein, virtual screening was performed and 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives were designed, synthesized as antineoplastic agents, and evaluated for their anti-tumor activities. Among them, the most promising compound H1 showed specific anti-proliferation ability against HeLa cells (IC = 380 nM) as well as excellent inhibition of tumor growth in the HeLa xenograft model without inducing obvious side effects. It is interesting that compound H1 displayed significant inhibition against HPV18-positive cervical cell lines (HeLa) but not for HPV16-positive cervical cell lines (SiHa). Further study demonstrated that a low concentration of compound H1 could lead to a cell cycle blockage at the G1 phase and promote cell apoptosis slightly (8.77%). Compound H1 also exhibited transcription repression, especially those associated with the oncoprotein E7 cellular pathway like E7/Rb/E2F-1/DNMT1, which were essential in tumorigenesis. Proteomics analysis revealed that E7 might be degraded through E3 ubiquitin ligases, which aligned with decreasing expression of E7 following the treatment of compound H1. Taken together, it indicated that compound H1 could be a promising potential agent for cervical cancer treatment.
Peili Jiao, Yuxi Wang, Beibei Mao, Bingding Wang, Yi Zhong, Hongwei Jin, Lihe Zhang, Liangren Zhang, Zhenming Liu

2551 related Products with: Discovery of 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives that regulated HPV relevant cellular pathway and prevented cervical cancer from abnormal proliferation.

2 Pieces/Box

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#32739133   2020/04/27 To Up

Expanding molecular roles of UV-DDB: Shining light on genome stability and cancer.

UV-damaged DNA binding protein (UV-DDB) is a heterodimeric complex, composed of DDB1 and DDB2, and is involved in global genome nucleotide excision repair. Mutations in DDB2 are associated with xeroderma pigmentosum complementation group E. UV-DDB forms a ubiquitin E3 ligase complex with cullin-4A and RBX that helps to relax chromatin around UV-induced photoproducts through the ubiquitination of histone H2A. After providing a brief historical perspective on UV-DDB, we review our current knowledge of the structure and function of this intriguing repair protein. Finally, this article discusses emerging data suggesting that UV-DDB may have other non-canonical roles in base excision repair and the etiology of cancer.
Maria Beecher, Namrata Kumar, Sunbok Jang, Vesna Rapić-Otrin, Bennett Van Houten

1950 related Products with: Expanding molecular roles of UV-DDB: Shining light on genome stability and cancer.

100.00 ug96T200 96 wells (1 kit)

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