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https://www.readbyqxmd.com/read/28835500/hpv-16-hpv-18-and-hpv-31-e6-override-the-normal-phospho-regulation-of-e6ap-enzymatic-activity
#1
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 auto-ubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a PKA phospho-acceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study we have analysed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates...
August 23, 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
#2
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
#3
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...
June 1, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28477016/e6ap-promotes-prostate-cancer-by-reducing-p27-expression
#4
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
#5
Michael E French, Julian L Klosowiak, Aaron Aslanian, Steven I Reed, John R Yates, Tony Hunter
Homologous to E6AP C-terminal (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). Our results demonstrate that WWP1 catalyzes the formation of Ub chains through a sequential addition mechanism, in which Ub monomers are transferred in a successive fashion to the substrate, and that ubiquitination by WWP1 requires the presence of a low-affinity, noncovalent Ub-binding site within the HECT domain...
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28326016/early-origin-and-evolution-of-the-angelman-syndrome-ubiquitin-ligase-gene-ube3a
#8
REVIEW
Masaaki Sato
The human Ube3a gene encodes an E3 ubiquitin ligase and exhibits brain-specific genomic imprinting. Genetic abnormalities that affect the maternal copy of this gene cause the neurodevelopmental disorder Angelman syndrome (AS), which is characterized by severe mental retardation, speech impairment, seizure, ataxia and some unique behavioral phenotypes. In this review article, I highlight the evolution of the Ube3a gene and its imprinting to provide evolutionary insights into AS. Recent comparative genomic studies have revealed that Ube3a is most phylogenetically similar to HECTD2 among the human HECT (homologous to the E6AP carboxyl terminus) family of E3 ubiquitin ligases, and its distant evolutionary origin can be traced to common ancestors of fungi and animals...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28214999/e6-associated-protein-dependent-estrogen-receptor-regulation-of-protein-kinase-a-regulatory-subunit-r2a-expression-in-neuroblastoma
#9
Jean-Pierre Obeid, Youssef H Zeidan, Nawal Zafar, Jimmy El Hokayem
E6ap is a known transcriptional coregulator for estrogen receptor alpha (Er, Erα) in the presence of estrogen. Protein kinase A (PKA) contains two regulatory subunits derived from four genes. Recent evidence demonstrates that PKA regulates E6ap activity. Data generated in our lab indicated estrogen dependent regulation of Pkar2a levels. Our project sets to investigate a possible feedback mechanism constituting of Erα and E6ap transcriptional regulation of Pkar2a expression. Western blot evaluated protein regulation correlations with E2 in mouse neuroblastoma lines...
February 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28074012/reduced-abundance-of-the-e3-ubiquitin-ligase-e6ap-contributes-to-decreased-expression-of-the-ink4-arf-locus-in-non-small-cell-lung-cancer
#10
Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B Fox, Prudence Russell, Doron Ginsberg, Brendon J Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt
The tumor suppressor p16(INK4a), one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15(INK4b), p16(INK4a), and p19(ARF)) was decreased in E6AP(-/-) mouse embryo fibroblasts...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/27902328/hepatitis-c-virus-core-activates-proteasomal-activator-28%C3%AE-expression-via-upregulation-of-p53-levels-to-control-virus-propagation
#11
Juri Kwak, Indira Tiwari, Kyung Lib Jang
The proteasomal activator 28γ (PA28γ), frequently overexpressed in hepatocellular carcinoma, is believed to play several important roles in hepatitis C virus (HCV) replication and viral pathogenesis. However, the underlying mechanism for PA28γ overexpression in hepatocellular carcinoma and its role during HCV replication are still unclear. In the present study, we found that HCV core derived from either ectopic expression or HCV infection upregulates PA28γ levels in p53-positive human hepatocytes. For this effect, HCV core sequentially activated ataxia telangiectasia mutated and checkpoint kinase 2 via phosphorylation at Ser-1981 and Thr-68 residues, respectively, resulting in stabilization of p53 via phosphorylation at Ser-15 and Ser-20 residues and subsequent transcriptional activation of PA28γ expression...
January 2017: Journal of General Virology
https://www.readbyqxmd.com/read/27902311/ubiquitin-ligase-e6ap-mediates-nonproteolytic-polyubiquitylation-of-%C3%AE-catenin-independent-of-the-e6-oncoprotein
#12
Yael Kuslansky, Sophia Sominsky, Anna Jackman, Cristina Gamell, Brendon J Monahan, Ygal Haupt, Rina Rosin-Arbesfeld, Levana Sherman
Recently, we showed that the ubiquitin ligase E6AP stabilizes β-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study, we explored the function of E6AP, which increases β-catenin stabilization and transcriptional activation. Here, we report that E6AP interacts with β-catenin and mediates its nonproteolytic ubiquitylation, as evidenced in transiently transfected cell-based and in vitro reconstitution ubiquitylation assays...
December 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27641331/restoration-of-tumor-suppression-in-prostate-cancer-by-targeting-the-e3-ligase-e6ap
#13
P J Paul, D Raghu, A-L Chan, T Gulati, L Lambeth, E Takano, M J Herold, J Hagekyriakou, R L Vessella, C Fedele, M Shackleton, E D Williams, S Fox, S Williams, S Haupt, C Gamell, Y Haupt
Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC)...
December 1, 2016: Oncogene
https://www.readbyqxmd.com/read/27619993/progranulin-controls-sepsis-via-c-ebp%C3%AE-regulated-il10-transcription-and-ubiquitin-ligase-proteasome-mediated-protein-degradation
#14
Wenjun Yan, Aihao Ding, Ha-Jeong Kim, Hua Zheng, Fang Wei, Xiaojing Ma
Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes, including cellular proliferation, neuron development, and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. In this study, we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27527792/regulation-of-the-mei-1-mei-2-microtubule-severing-katanin-complex-in-early-caenorhabditis-elegans-development
#15
Sarah M Beard, Ryan B Smit, Benjamin G Chan, Paul E Mains
After fertilization, rapid changes of the Caenorhabditis elegans cytoskeleton occur in the transition from meiosis to mitosis, requiring precise regulation. The MEI-1/MEI-2 katanin microtubule-severing complex is essential for meiotic spindle formation but must be quickly inactivated to allow for proper formation of the mitotic spindle. MEI-1/MEI-2 inactivation is dependent on multiple redundant pathways. The primary pathway employs the MEL-26 substrate adaptor for the CUL-3/cullin-based E3 ubiquitin ligase, which targets MEI-1 for proteosomal degradation...
October 13, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27322423/a-recombinant-chimeric-protein-specifically-induces-mutant-kras-degradation-and-potently-inhibits-pancreatic-tumor-growth
#16
Ting Pan, Yiwen Zhang, Nan Zhou, Xin He, Cancan Chen, Liting Liang, Xiaobing Duan, Yingtong Lin, Kang Wu, Hui Zhang
Pancreatic cancer is one of the most lethal human diseases, with an all-stage 5-year survival rate below 5%. To date, no effective and specific therapy is available for this disease. Mutations in KRAS are frequently reported in pancreatic and many other cancers; thus, KRAS is an attractive therapeutic target. Our objective was to specifically eliminate mutant KRAS and induce cell death of tumors expressing this mutant protein. We thus constructed several chimeric proteins by connecting the C-terminal domains of several adaptor proteins of E3 ubiquitin ligases such as CBL, CHIP, E6AP, and VHL, as well as VIF encoded by human immunodeficiency virus type 1 (HIV-1), to the Ras binding domain (RBD) of Raf...
July 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27317649/hepatitis-c-virus-core-protein-inhibits-e6ap-expression-via-dna-methylation-to-escape-from-ubiquitin-dependent-proteasomal-degradation
#17
Juri Kwak, Joo Hee Shim, Indira Tiwari, Kyung Lib Jang
The E6-associated protein (E6AP) is a ubiquitin ligase that mediates ubiquitination and proteasomal degradation of hepatitis C virus (HCV) core protein. Given the role of HCV core protein as a major component of the viral nucleocapsid, as well as a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis, HCV has likely evolved a strategy to counteract the host anti-viral defense mechanism of E6AP and maximize its potential to produce infectious virus particles. In the present study, we found that HCV core protein derived from either ectopic expression or HCV infection inhibits E6AP expression via promoter hypermethylation in human hepatocytes...
September 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27240147/hpv16-e6-regulates-annexin-1-anxa1-protein-expression-in-cervical-carcinoma-cell-lines
#18
Marilia Freitas Calmon, Laura Sichero, Enrique Boccardo, Luisa Lina Villa, Paula Rahal
Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt...
September 2016: Virology
https://www.readbyqxmd.com/read/27231202/the-e3-ligase-e6ap-represses-breast-cancer-metastasis-via-regulation-of-ect2-rho-signaling
#19
Mariam Mansour, Sue Haupt, Ai-Leen Chan, Nathan Godde, Alexandra Rizzitelli, Sherene Loi, Franco Caramia, Siddhartha Deb, Elena A Takano, Mark Bishton, Cameron Johnstone, Brendon Monahan, Yarra Levav-Cohen, Yong-Hui Jiang, Alpha S Yap, Stephen Fox, Ora Bernard, Robin Anderson, Ygal Haupt
Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors...
July 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27142689/grim-19-restores-cervical-cancer-cell-senescence-by-repressing-htert-transcription
#20
Ying Zhou, Fei Xu, Feng Tao, Dingqing Feng, Bin Ling, Lili Qian, Xia Yang, Qingyuan Wang, Huiyan Wang, Weidong Zhao, Yong Cheng, Ge Shan, Dhan V Kalvakolanu, Weihua Xiao
High telomerase activity promotes tumor growth by stabilizing damaged chromosomes and their mitotic replication. Overactivation of telomerase activity has been reported in cervical cancer, a malignancy caused by high-risk human papillomaviruses (HR-HPVs). The HR-HPV E6 can activate hTERT promoter by interacting with E6AP or other binding proteins and by stabilizing the interaction between hTERT and E6AP. GRIM-19 is a novel tumor suppressor that affects multiple targets in a cell to regulate growth. We have previously reported the interaction of GRIM-19 with 18E6 and E6AP to disrupt the E6/E6AP complex and increase the autoubiquitination of E6AP...
August 2016: Journal of Interferon & Cytokine Research
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