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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 ubiquitinconjugating 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...
March 27, 2017: Annual Review of Biochemistry
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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...
January 21, 2016: Cell Death & Disease
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
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
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