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https://www.readbyqxmd.com/read/29487861/a-versatile-plasmid-system-for-reconstitution-and-analysis-of-mammalian-ubiquitination-cascades-in-yeast
#1
Rossella Avagliano Trezza, Janny van den Burg, Nico van den Oever, Ben Distel
Ubiquitination is a posttranslational protein modification that regulates most aspects of cellular life. The sheer number of ubiquitination enzymes that are present in a mammalian cell, over 700 in total, has thus far hampered the analysis of distinct protein ubiquitination cascades in a cellular context. To overcome this complexity we have developed a versatile vector system that allows the reconstitution of specific ubiquitination cascades in the model eukaryote Saccharomyces cerevisae (baker's yeast). The vector system consists of 32 modular yeast shuttle plasmids allowing inducible or constitutive expression of up to four proteins of interest in a single cell...
December 5, 2017: Microbial Cell
https://www.readbyqxmd.com/read/29463595/proteotranscriptomic-measurements-of-e6-associated-protein-e6ap-targets-in-du145-prostate-cancer-cells
#2
Twishi Gulati, Cheng Huang, Franco Caramia, Dinesh Raghu, Piotr Jan Paul, Robert J A Goode, Simon Paul Keam, Scott G Williams, Sue Haupt, Oded Kleifeld, Ralf B Schittenhelm, Cristina Gamell, Ygal Haupt
Prostate cancer is a common cause of cancer-related death in men. E6AP (E6-Associated Protein), an E3 ubiquitin ligase and a transcription cofactor, is elevated in a subset of prostate cancer patients. Genetic manipulations of E6AP in prostate cancer cells expose a role of E6AP in promoting growth and survival of prostate cancer cells in vitro and in vivo. However, the effect of E6AP on prostate cancer cells is broad and it cannot be explained fully by previously identified tumour suppressor targets of E6AP, promyelocytic leukemia protein and p27...
February 20, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29426014/network-analysis-of-ube3a-e6ap-associated-proteins-provides-connections-to-several-distinct-cellular-processes
#3
Gustavo Martínez-Noël, Katja Luck, Simone Kühnle, Alice Desbuleux, Patricia Szajner, Jeffrey T Galligan, Diana Rodriguez, Leon Zheng, Kathleen Boyland, Flavian Leclere, Quan Zhong, David E Hill, Marc Vidal, Peter M Howley
Perturbations in activity and dosage of the UBE3A ubiquitin-ligase have been linked to Angelman syndrome and autism spectrum disorders. UBE3A was initially identified as the cellular protein hijacked by the human papillomavirus E6 protein to mediate the ubiquitylation of p53, a function critical to the oncogenic potential of these viruses. Although a number of substrates have been identified, the normal cellular functions and pathways affected by UBE3A are largely unknown. Previously, we showed that UBE3A associates with HERC2, NEURL4, and MAPK6/ERK3 in a high-molecular-weight complex of unknown function that we refer to as the HUN complex (HERC2, UBE3A, and NEURL4)...
March 30, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29388081/loss-of-angelman-syndrome-protein-e6ap-disrupts-a-novel-antagonistic-estrogen-retinoic-acid-transcriptional-crosstalk-in-neurons
#4
Jimmy El Hokayem, Edwin Weeber, Zafar Nawaz
Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2-15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A, which is located in this region, and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e...
January 31, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29339538/e6-protein-expressed-by-high-risk-hpv-activates-super-enhancers-of-the-egfr-and-c-met-oncogenes-by-destabilizing-the-histone-demethylase-kdm5c
#5
Xiaohua Chen, Jun Xian Loo, Xin Shi, Wenjun Xiong, Yong Guo, Haiqiang Ke, Mingkun Yang, Yanping Jiang, Siyu Xia, Min Zhao, Shan Zhong, Chunjiang He, Li Fu, Feng Li
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner...
March 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29288669/ubiquitin-chain-specificities-of-e6ap-e3-ligase-and-its-hect-domain
#6
Fuminori Kobayashi, Takumi Nishiuchi, Kento Takaki, Hiroki Konno
Ubiquitination of target proteins is accomplished by isopeptide bond formation between the carboxy group of the C-terminal glycine (Gly) residue of ubiquitin (Ub) and the ɛ-amino group of lysine (Lys) on the target proteins. The formation of an isopeptide bond between Ubs that gives rise to a poly-Ub chain on the target proteins and the types of poly-Ub chains formed depend on which of the seven Lys residues or N-terminal methionine (Met) residue on Ub is used for chain elongation. To understand the linkage specificity mechanism of Ub chains on E3, the previous study established an assay to monitor the formation of a free diubiquitin chain (Ub2 chain synthesis assay) by HECT type E3 ligase...
February 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29281732/association-of-papillomavirus-e6-proteins-with-either-maml1-or-e6ap-clusters-e6-proteins-by-structure-function-and-evolutionary-relatedness
#7
Nicole Brimer, Camille M Drews, Scott B Vande Pol
Papillomavirus E6 proteins bind to LXXLL peptide motifs displayed on targeted cellular proteins. Alpha genus HPV E6 proteins associate with the cellular ubiquitin ligase E6AP (UBE3A), by binding to an LXXLL peptide (ELTLQELLGEE) displayed by E6AP, thereby stimulating E6AP ubiquitin ligase activity. Beta, Gamma, and Delta genera E6 proteins bind a similar LXXLL peptide (WMSDLDDLLGS) on the cellular transcriptional co-activator MAML1 and thereby repress Notch signaling. We expressed 45 different animal and human E6 proteins from diverse papillomavirus genera to ascertain the overall preference of E6 proteins for E6AP or MAML1...
December 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29274324/apoptosis-induction-and-inhibition-of-hela-cell-proliferation-by-alpha-naphthoflavone-and-resveratrol-are-aryl-hydrocarbon-receptor-independent
#8
Alegre Flores-Pérez, Guillermo Elizondo
Human papilloma viruses 16 and 18 express E6 and E7 oncoproteins. E6 activates and redirects E6-associated protein (E6AP), an E3 ubiquitin ligase. E6AP interacts with Ube2l3, an E2 ubiquitin conjugating enzyme protein (also known as UbcH7), to promote p53 ubiquitination and degradation by the 26S proteasome. Therefore, blocking E6-mediated p53 degradation might be an alternative treatment for cervical cancer. In addition, activation of the aryl hydrocarbon receptor (AHR) induces Ube2l3 expression, resulting in p53 ubiquitination and degradation...
February 1, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29202468/polycomb-subunit-bmi1-determines-uterine-progesterone-responsiveness-essential-for-normal-embryo-implantation
#9
Qiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, Haibin Wang
Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29175955/the-autism-protein-ube3a-e6ap-remodels-neuronal-dendritic-arborization-via-caspase-dependent-microtubule-destabilization
#10
Natasha Khatri, James P Gilbert, Yuda Huo, Roozhin Sharaflari, Michael Nee, Hui Qiao, Heng-Ye Man
UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites...
January 10, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29054411/e6ap-ube3a-catalyzes-encephalomyocarditis-virus-3c-protease-polyubiquitylation-and-promotes-its-concentration-reduction-in-virus-infected-cells
#11
Marybeth Carmody, Tara P Notarianni, Larissa A Sambel, Shannon J Walsh, Jenna M Burke, Jenna L Armstrong, T Glen Lawson
The encephalomyocarditis virus (EMCV) 3C protease (3Cpro ) is one of a small number of viral proteins whose concentration is known to be regulated by the cellular ubiquitin-proteasome system. Here we report that the ubiquitin-conjugating enzyme UbcH7/UBE2L3 and the ubiquitin-protein ligase E6AP/UBE3A are components of a previously unknown EMCV 3Cpro -polyubiquitylating pathway. Following the identification of UbcH7/UBE2L3 as a participant in 3Cpro ubiquitylation, we purified a UbcH7-dependent 3Cpro -ubiquitylating activity from mouse cells, which we identified as E6AP...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28972136/the-mechanism-of-neural-precursor-cell-expressed-developmentally-down-regulated-4-2-nedd4-2-nedd4l-catalyzed-polyubiquitin-chain-assembly
#12
Dustin R Todaro, Allison C Augustus-Wallace, Jennifer M Klein, Arthur L Haas
The mechanism of Nedd4-2 has been quantitatively explored for the first time using biochemically defined kinetic assays examining rates of125 I-polyubiquitin chain assembly as a functional readout. We demonstrate that Nedd4-2 exhibits broad specificity for E2 paralogs of the Ubc4/5 clade to assemble Lys63 -linked polyubiquitin chains. Full-length Nedd4-2 catalyzes free125 I-polyubiquitin chain assembly by hyperbolic Michaelis-Menten kinetics with respect to Ubc5B∼ubiquitin thioester concentration ( Km = 44 ± 6 nm; k cat = 0...
November 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28924046/-in-silico-modeling-of-the-cryptic-e2%C3%A2-ubiquitin-binding-site-of-e6-associated-protein-e6ap-ube3a-reveals-the-mechanism-of-polyubiquitin-chain-assembly
#13
Virginia P Ronchi, Elizabeth D Kim, Christopher M Summa, Jennifer M Klein, Arthur L Haas
To understand the mechanism for assembly of Lys48 -linked polyubiquitin degradation signals, we previously demonstrated that the E6AP/UBE3A ligase harbors two functionally distinct E2∼ubiquitin-binding sites: a high-affinity Site 1 required for E6AP Cys820 ∼ubiquitin thioester formation and a canonical Site 2 responsible for subsequent chain elongation. Ordered binding to Sites 1 and 2 is here revealed by observation of UbcH7∼ubiquitin-dependent substrate inhibition of chain formation at micromolar concentrations...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28835500/human-papillomavirus-16-hpv-16-hpv-18-and-hpv-31-e6-override-the-normal-phosphoregulation-of-e6ap-enzymatic-activity
#14
Jayashree Thatte, Lawrence Banks
The human papillomavirus (HPV) E6 oncoproteins recruit the cellular ubiquitin ligase E6AP/UBE3A to target cellular substrates for proteasome-mediated degradation, and one consequence of this activity is the E6 stimulation of E6AP autoubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a protein kinase A phosphoacceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study, we have analyzed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28586650/e6-proteins-of-%C3%AE-and-%C3%AE-cutaneous-hpv-types-differ-in-their-ability-to-potentiate-wnt-signaling
#15
Sophia Sominsky, Naama Shterzer, Anna Jackman, Beny Shapiro, Abraham Yaniv, Levana Sherman
We recently showed that E6 protein of human papillomavirus (HPV) 16, a mucosal high-risk α-PV type, can potentiate Wnt/β-catenin/TCF signaling. Here we investigated the transcriptional activities of E6 proteins of cutaneous HPV types from the β and α genera. Results from reporter-gene assays showed that similar to HPV16 E6, E6 of HPV10, a cutaneous α-HPV type that is prevalent in skin warts, efficiently enhances and stimulates Wnt/β-catenin/TCF transcription. HPV10 E6 also effectively elevated the expression levels of β-catenin and promoted its nuclear accumulation...
September 2017: Virology
https://www.readbyqxmd.com/read/28578910/e6ap-inhibits-g-csfr-turnover-and-functions-by-promoting-its-ubiquitin-dependent-proteasome-degradation
#16
Stuti Chhabra, Yogesh Kumar, Gatha Thacker, Isha Kapoor, Savita Lochab, Sabyasachi Sanyal, Madan L B Bhatt, Naibedya Chattopadhyay, Arun Kumar Trivedi
Granulocyte colony-stimulating factor receptor (G-CSFR) plays a crucial role in regulating myeloid cell survival, proliferation, and neutrophilic granulocyte precursor cells maturation. Previously, we demonstrated that Fbw7α negatively regulates G-CSFR and its downstream signaling through ubiquitin-proteasome mediated degradation. However, whether additional ubiquitin ligases for G-CSFR exist is not known. Identifying multiple E3 ubiquitin ligases for G-CSFR shall improve our understanding of activation and subsequent attenuation of G-CSFR signaling required for differentiation and proliferation...
October 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28477016/e6ap-promotes-prostate-cancer-by-reducing-p27-expression
#17
Dinesh Raghu, Piotr Jan Paul, Twishi Gulati, Siddhartha Deb, Christine Khoo, Andrea Russo, Enzo Gallo, Giovanni Blandino, Ai-Leen Chan, Elena Takano, Shahneen K Sandhu, Stephen B Fox, Scott Williams, Sue Haupt, Cristina Gamell, Ygal Haupt
Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28461335/mechanism-of-ubiquitin-chain-synthesis-employed-by-a-hect-domain-ubiquitin-ligase
#18
Michael E French, Julian L Klosowiak, Aaron Aslanian, Steven I Reed, John R Yates, Tony Hunter
<u>H</u> omologous to<u>E</u>6AP<u>C</u>-<u>t</u>erminal (HECT) ubiquitin (Ub) ligases (E3s) are a large class of enzymes that bind to their substrates and catalyze ubiquitination through the formation of a Ub thioester intermediate. The mechanisms by which these E3s assemble polyubiquitin chains on their substrates remain poorly defined. We report here that the Nedd4 family HECT E3, WWP1, assembles substrate-linked Ub chains containing Lys-63, Lys-48, and Lys-11 linkages (Lys-63 > Lys-48 > Lys-11)...
June 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28440909/roles-of-the-pdz-binding-motif-of-hpv-16-e6-protein-in-oncogenic-transformation-of-human-cervical-keratinocytes
#19
Yuki Yoshimatsu, Tomomi Nakahara, Katsuyuki Tanaka, Yuki Inagawa, Mako Narisawa-Saito, Takashi Yugawa, Shin-Ichi Ohno, Masatoshi Fujita, Hitoshi Nakagama, Tohru Kiyono
The high-risk human papillomavirus E6 proteins have been shown to interact with and lead to degradation of PDZ-domain-containing proteins through its carboxy-terminal motif. This PDZ-binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6-transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an in vitro carcinogenesis model for cervical cancer, in which E6 and E7 together with activated HRAS (HRAS(G)(12V) ) can induce tumorigenic transformation of normal human cervical keratinocytes...
July 2017: Cancer Science
https://www.readbyqxmd.com/read/28375744/ubiquitin-ligases-structure-function-and-regulation
#20
REVIEW
Ning Zheng, Nitzan Shabek
Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. Recent studies have provided deeper mechanistic insights into their catalysis, activation, and regulation...
June 20, 2017: Annual Review of Biochemistry
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