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https://www.readbyqxmd.com/read/27902328/hepatitis-c-virus-core-activates-proteasomal-activator-28-gamma-expression-via-upregulation-of-p53-levels-to-control-virus-propagation
#1
Juri Kwak, Indira Tiwari, Kyung Lib Jang
The proteasomal activator PA28γ, frequently overexpressed in hepatocellular carcinoma (HCC), is believed to play several important roles in hepatitis C virus (HCV) replication and viral pathogenesis. However, the underlying mechanism for PA28γ overexpression in HCC 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...
November 11, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27902311/the-ubiquitin-ligase-e6ap-mediates-nonproteolytic-polyubiquitylation-of-%C3%AE-catenin-independent-of-the-e6-oncoprotein
#2
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 that 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...
October 7, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27641331/restoration-of-tumor-suppression-in-prostate-cancer-by-targeting-the-e3-ligase-e6ap
#3
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
#4
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
#5
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
#6
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...
June 14, 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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/27124407/a-high-throughput-cell-based-screen-identified-a-2-e-2-phenylvinyl-8-quinolinol-core-structure-that-activates-p53
#11
John Bechill, Rong Zhong, Chen Zhang, Elena Solomaha, Michael T Spiotto
p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53...
2016: PloS One
https://www.readbyqxmd.com/read/27079945/ap1s3-is-required-for-hepatitis-c-virus-infection-by-stabilizing-e2-protein
#12
Xiang Li, Yuqiang Niu, Min Cheng, Xiaojing Chi, Xiuying Liu, Wei Yang
Hepatitis C virus (HCV) infects 130 million people worldwide and is a leading cause of liver cirrhosis, end-stage liver disease and hepatocellular carcinoma. The interactions between viral elements and host factors play critical role on HCV invade, replication and release. Here, we identified adaptor protein complex 1 sigma 3 subunit (AP1S3) as a dependency factor for the efficient HCV infection in hepatoma cells. AP1S3 silencing in cultivated Huh7.5.1 cells significantly reduced the production of HCV progeny particles...
July 2016: Antiviral Research
https://www.readbyqxmd.com/read/26915086/molecular-probing-of-the-hpv-16-e6-protein-alpha-helix-binding-groove-with-small-molecule-inhibitors
#13
Anne Rietz, Dino P Petrov, Matthew Bartolowits, Marsha DeSmet, V Jo Davisson, Elliot J Androphy
The human papillomavirus (HPV) HPV E6 protein has emerged as a central oncoprotein in HPV-associated cancers in which sustained expression is required for tumor progression. A majority of the E6 protein interactions within the human proteome use an alpha-helix groove interface for binding. The UBE3A/E6AP HECT domain ubiquitin ligase binds E6 at this helix-groove interface. This enables formation of a trimeric complex with p53, resulting in destruction of this tumor suppressor. While recent x-ray crystal structures are useful, examples of small molecule probes that can modulate protein interactions at this interface are limited...
2016: PloS One
https://www.readbyqxmd.com/read/26794656/flavonol-and-imidazole-derivatives-block-hpv16-e6-activities-and-reactivate-apoptotic-pathways-in-hpv%C3%A2-%C2%BA-cells
#14
C-H Yuan, M Filippova, J L Krstenansky, P J Duerksen-Hughes
High-risk human papillomaviruses (HR-HPVs) cause nearly all cases of cervical cancer, as well as approximately 30% of head and neck cancers. HPV 16 E6, one of two major viral oncogenes, protects cells from apoptosis by binding to and accelerating the degradation of several proteins important in apoptotic signaling, including caspase 8 and p53. We proposed that blocking the interactions between HPV E6 and its partners using small molecules had the potential to re-sensitize HPV(+) cells to apoptosis. To test this idea, we screened libraries of small molecules for candidates that could block E6/caspase 8 binding and identified several candidates from different chemical classes...
2016: Cell Death & Disease
https://www.readbyqxmd.com/read/26789255/structure-of-the-e6-e6ap-p53-complex-required-for-hpv-mediated-degradation-of-p53
#15
Denise Martinez-Zapien, Francesc Xavier Ruiz, Juline Poirson, André Mitschler, Juan Ramirez, Anne Forster, Alexandra Cousido-Siah, Murielle Masson, Scott Vande Pol, Alberto Podjarny, Gilles Travé, Katia Zanier
The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown...
January 28, 2016: Nature
https://www.readbyqxmd.com/read/26506232/proteomic-discovery-of-mnt-as-a-novel-interacting-partner-of-e3-ubiquitin-ligase-e6ap-and-a-key-mediator-of-myeloid-differentiation
#16
Isha Kapoor, Jitendra Kanaujiya, Yogesh Kumar, Jagadeshwar Reddy Thota, Madan L B Bhatt, Naibedya Chattopadhyay, Sabyasachi Sanyal, Arun Kumar Trivedi
Perturbed stability of regulatory proteins is a major cause of transformations leading to cancer, including several leukemia subtypes. Here, for the first time we demonstrate that E6-associated protein (E6AP), an E3 ubiquitin ligase negatively targets MAX binding protein MNT for ubiquitin-mediated proteasome degradation and impedes ATRA mediated myeloid cell differentiation. MNT is a member of the Myc/Max/Mad network of transcription factor that regulates cell proliferation, differentiation, cellular transformation and tumorigenesis...
February 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/26363225/breast-cancer-cells-modulation-by-melatonin-and-the-ubiquitin-proteasome-system-a-review
#17
REVIEW
Jerry Vriend, Russel J Reiter
Melatonin inhibits human breast cancer cells stimulated with estrogen. This antiproliferative action depends on the presence of the estrogen receptor alpha (ERα) in the human MCF-7 cell line and is strictly dose-dependent. Since researchers concerned with melatonin and breast cancer have not considered the relevance of the ubiquitin-proteasome system to this research in this review we do so. The fact that the first breast cancer susceptibility gene to be identified, Brca1, functions as a ubiquitin ligase indicates that the ubiquitin-proteasome system has a role in regulating susceptibility to breast cancer...
December 5, 2015: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/26318036/cop9-signalosome-subunit-6-csn6-regulates-e6ap-ube3a-in-cervical-cancer
#18
Shujun Gao, Lekun Fang, Liem Minh Phan, Aiham Qdaisat, Sai-Ching J Yeung, Mong-Hong Lee
Cervical cancer is one of the leading causes of cancer death in women. Human papillomaviruses (HPVs) are the major cause in almost 99.7% of cervical cancer. E6 oncoprotein of HPV and E6-associated protein (E6AP) are critical in causing p53 degradation and malignancy. Understanding the E6AP regulation is critical to develop treating strategy for cervical cancer patients. The COP9 signalosome subunit 6 (CSN6) is involved in ubiquitin-mediated protein degradation. We found that both CSN6 and E6AP are overexpressed in cervical cancer...
September 29, 2015: Oncotarget
https://www.readbyqxmd.com/read/26261538/impact-of-e6-associated-protein-on-the-proliferation-and-invasion-of-prostate-cancer-cells-in-bone-metastasis
#19
Liyan Zhang, Xiaoguang Hu, Jiying Chen, Guilian Fu
PURPOSE: To understand E6 associated protein (E6-AP)'s influence on prostate cancer cell proliferation and infiltration, thus providing the theoretical basis for developing therapeutic drugs for prostate cancer metastasis to the bone. METHODS: Electroporation was performed to introduce linear regulatory plasmid PrevTet-off-in and conjugative plasmid PrevTRE2-flag-E6AP into prostate cancer cell line to establish wild-type E6-AP over-expressing transgenic LNCaP cell line; Western blot assay was adopted to examine expression levels of E6-AP, mammalian target of rapamycin (mTOR), protein kinase B (Akt), and phosphoinositide 3-kinase (PI3K); PI3K inhibitor LY294002 was applied to all the cells and MTT assay was used to measure cell proliferation; Matrigel invasion chamber assay was adopted to detect cancer cell migration and invasion...
2015: International Journal of Clinical and Experimental Pathology
https://www.readbyqxmd.com/read/26234678/e3-ligase-edd1-ubr5-is-utilized-by-the-hpv-e6-oncogene-to-destabilize-tumor-suppressor-tip60
#20
V K Subbaiah, Y Zhang, D Rajagopalan, L N Abdullah, N S L Yeo-Teh, V Tomaić, L Banks, M P Myers, E K Chow, S Jha
Tat-interacting protein of 60 kDa (TIP60) is an essential lysine acetyltransferase implicated in transcription, DNA damage response and apoptosis. TIP60 protein expression is reduced in cancers. In cervical cancers, human papillomavirus (HPV) E6 oncogene targets cellular p53, Bak and some of the PDZ domain-containing proteins for proteasome-mediated degradation through E6AP ligase. Recently, E6 oncogene from high-risk and low-risk categories was also shown to target TIP60. However, the molecular mechanisms and whether destabilization of TIP60 contributes to HPV E6-mediated transformation remain unanswered...
April 21, 2016: Oncogene
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