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Filomena Grosso, Peter Stoilov, Clifford Lingwood, Martha Brown, Alan Cochrane
: The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome, potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yield of four adenoviruses (HAdV-A31, B35, C5 and a species D conjunctivitis isolate) by at least 2- 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein, hexon, are compromised...
November 23, 2016: Journal of Virology
Yunfei Wang, Dawei Li, Jian Luo, Guimei Tian, Lisa Y Zhao, Daiqing Liao
Cancer cells of epithelial and mesenchymal phenotypes exhibit different sensitivities to apoptosis stimuli, but the mechanisms underlying this phenomenon remain partly understood. We constructed a novel recombinant adenovirus expressing Ad12 E1A (Ad-E1A12) that can strongly induce apoptosis. Ad-E1A12 infection of epithelial cancer cells displayed dramatic detachment and apoptosis, whereas cancer cells of mesenchymal phenotypes with metastatic propensity were markedly more resistant to this virus. Notably, forced detachment of epithelial cells did not further sensitize them to Ad-E1A12-induced apoptosis, suggesting that cell detachment is a consequence rather than the cause of Ad-E1A12-induced apoptosis...
November 16, 2016: Scientific Reports
X Pan, X Liu, J Li, S Zhen, D Liu, Q Feng, W Zhao, Y Luo, Y Zhang, H Li, J Yang
Ras mutations and overexpression of the Ras protein; i.e., p21Ras, are main causes of cancer development and progression, which has made the Ras gene and p21Ras important targets for therapy of Ras-driven cancers. We previously prepared recombinant adenovirus KGHV100 based on replication-defective adenovirus type 5, which could intracellularly express anti-p21Ras single chain fragment viable antibodies (scFv) and repress tumor growth in vitro and in vivo. However, the anti-tumor effects of this anti-p21Ras scFv were limited by short-term scFv expression due to a replication defect of KGHV100...
November 11, 2016: Gene Therapy
Jay R Radke, Zeba K Siddiqui, Iris Figueroa, James L Cook
Expression of the adenoviral protein, E1A, sensitizes mammalian cells to a wide variety of apoptosis-inducing agents through multiple cellular pathways. For example, E1A sensitizes cells to apoptosis induced by TNF-superfamily members by inhibiting NF-kappa B (NF-κB)-dependent gene expression. In contrast, E1A sensitization to nitric oxide, an inducer of the intrinsic apoptotic pathway, is not dependent upon repression of NF-κB-dependent transcription but rather is dependent upon caspase-2 activation. The latter observation suggested that E1A-induced enhancement of caspase-2 activation might be a critical factor in cellular sensitization to other intrinsic apoptosis pathway-inducing agents...
2016: Cell Death Discovery
Thomas Parzefall, Trevor Lucas, Martin Koenighofer, Reinhard Ramsebner, Alexandra Frohne, Shelly Czeiger, Wolf-Dieter Baumgartner, Christian Schoefer, Wolfgang Gstoettner, Klemens Frei
CONCLUSION: Alterations within a novel putative Exon 1a within the gap junction beta 2 (GJB2) gene may play a role in the development of genetic hearing impairment in Austria. OBJECTIVES: Mutations in the GJB2 gene are the most common cause of hereditary sensorineural deafness. Genome-wide screening for alternative transcriptional start sites in the human genome has revealed the presence of an additional GJB2 exon (E1a). This study tested the hypothesis of whether alternative GJB2 transcription involving E1a may play a role in the development of congenital sensorineural deafness in Austria...
November 9, 2016: Acta Oto-laryngologica
Thomas Speiseder, Helga Hofmann-Sieber, Estefanía Rodríguez, Anna Schellenberg, Nuray Akyüz, Judith Dierlamm, Thilo Spruss, Claudia Lange, Thomas Dobner
: Previous observations that human amniotic fluid cells (AFC) can be transformed by human adenovirus type 5 (HAdV-5) E1A/E1B oncogenes prompted us to identify the target cells in the AFC population that are susceptible for transformation. Our results demonstrate that one cell type corresponding to mesenchymal stem/stroma cells (hMSC), can be reproducibly transformed by HAdV-5 E1A/E1B oncogenes as efficient as primary rodent cultures. HAdV-5 E1-transformed hMSCs exhibit all properties commonly associated with a high grade of oncogenic transformation, including enhanced cell proliferation, anchorage-independent growth, increased growth rate, high telomerase activity as well as numerical and structural chromosomal aberrations...
October 19, 2016: Journal of Virology
Chenghui Yan, Xiaoxiang Tian
Atherosclerosis, a chronic inflammatory disease, is a major risk factor attributed to several important cardiovascular events, particularly coronary artery disease and stroke. The pathological process of atherosclerosis is considered to be dynamic and complicated, which involves into the interaction between a variety of cell types within arteries and cells that migrate into the wall. Human cellular repressor of E1A-stimulated genes (CREG) is original found as a transcription factor because it can antagonize transcriptional activation and cellular transformation induced by the adenovirus E1A oncoprotein...
October 26, 2016: Current Drug Targets
Jasmine Rae Frost, Oladunni Olanubi, Stephen Ka-Hon Cheng, Andrea Soriano, Leandro Crisostomo, Alennie Lopez, Peter Pelka
Human adenovirus infects terminally differentiated cells and to replicate it must induce S-phase. The chief architects that drive adenovirus-infected cells into S-phase are the E1A proteins, with 5 different isoforms expressed during infection. E1A remodels the infected cell by associating with cellular factors and modulating their activity. The C-terminus of E1A is known to bind to only a handful of proteins. We have identified a novel E1A C-terminus binding protein, Ku70 (XRCC6), which was found to bind directly within the CR4 of E1A from human adenovirus type 5...
October 18, 2016: Virology
Peter Haberz, Munehito Arai, Maria A Martinez-Yamout, H Jane Dyson, Peter E Wright
Many viruses deregulate the cell and force transcription of viral genes by competing with cellular proteins for binding to the transcriptional co-activators CREB-binding protein (CBP) and p300. Through its interactions with CBP/p300 and the retinoblastoma protein, the adenovirus (AdV) early region 1A (E1A) oncoprotein hijacks the cell cycle and, in rodents, transforms the cell; the mechanistic and structural basis for these effects remain unclear. In this study we compare the affinity of protein constructs from the E1A proteins from two adenovirus serotypes, non-oncogenic AdV5 and highly oncogenic AdV12, for binding to the nuclear receptor coactivator binding domain (NCBD) of CBP...
December 2016: Protein Science: a Publication of the Protein Society
Tobias A Popp, Cynthia Tallant, Catherine Rogers, Oleg Fedorov, Paul E Brennan, Susanne Müller, Stefan Knapp, Franz Bracher
CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein-protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112...
October 13, 2016: Journal of Medicinal Chemistry
Ling-Jun Zhao, Paul M Loewenstein, Maurice Green
The adenovirus E1A 243R oncoprotein targets TRRAP, a scaffold protein that assembles histone acetyltransferase (HAT) complexes, such as the NuA4/Tip60 complex which mediates transcriptional activity of the proto-oncogene MYC and helps determine the cancer cell phenotype. How E1A transforms cells through TRRAP remains obscure. We performed proteomic analysis with the N-terminal transcriptional repression domain of E1A 243R (E1A 1-80) and showed that E1A 1-80 interacts with TRRAP, p400, and three other members of the NuA4 complex - DMAP1, RUVBL1 and RUVBL2 - not previously shown to associate with E1A 243R...
December 2016: Virology
Jie Shi, Shengjun Fu, Li Wang, Yan Tao, Ronald Rodriguez, Zhiping Wang
Our previous work confirmed that the bladder cancer-specific oncolytic adenovirus Ad/PSCAE/UPII/E1A could selectively replicate in bladder cancer cells, thus causing specific tumor cell lysis. The replicative potential is a crucial factor in determining the therapeutic efficacy of oncolytic adenoviruses. However, viral replication is attenuated by the low-activity promoter that we used, thus compromising viral cytotoxicity. In this study, we investigated the effect of the cell cycle-dependent kinase inhibitor p21/Waf-1 on an adenovirus...
January 2017: Anti-cancer Drugs
Hongjuan Zhang, Fang Wang, Chunjie Mao, Zuncheng Zhang, Shengjun Fu, Jianzhong Lu, Zhenxing Zhai, Renju Li, Shuwen Li, Ron Rodriguez, Zhiping Wang
PURPOSE: Gene therapy combined with radiation has shown promising potential for the treatment of tumors. This paper aimed to clarify the synergistic effect of radiotherapy combined with the bladder cancer tissue-specific oncolytic adenovirus (Ad-PSCAE-UPII-E1A) on bladder cancer cells and to study the underlying synergy mechanisms of the combined treatment. MATERIALS AND METHODS: The Adenovirus carrying E1A under control of UPII promoter and prostate stem cell antigen enhancer (PSCAE) were successfully constructed...
October 14, 2016: International Journal of Radiation Biology
Chih-Ming Su, Ting-Yu Chang, Hui-Ping Hsu, Hui-Huang Lai, Jie-Ning Li, Yu-Jhen Lyu, Kuang-Tai Kuo, Ming-Te Huang, Jen-Liang Su, Pai-Sheng Chen
Epidermal growth factor receptor (EGFR) is commonly overexpressed in breast cancer and is associated with poor clinical outcomes; however, an increasing number of patients have shown a poor effective response to EGFR tyrosine kinase inhibitors (EGFR-TKI). Here, we found that AXL expression was positively correlated with poor progression in breast cancer patients. Suppression of AXL by an anti-tumor protein, E1A, enhanced EGFR-TKI (gefitinib, erlotinib and lapatinib) sensitization, resulting in significant inhibition of tumor growth in breast cancer cells...
August 31, 2016: Oncotarget
Asita Elengoe, Salehhuddin Hamdan
In this study, we explored the possibility of determining the synergistic interactions between nucleotide-binding domain (NBD) of Homo sapiens heat-shock 70 kDa protein (Hsp70) and E1A 32 kDa of adenovirus serotype 5 motif (PNLVP) in the efficiency of killing of tumor cells in cancer treatment. At present, the protein interaction between NBD and PNLVP motif is still unknown, but believed to enhance the rate of virus replication in tumor cells. Three mutant models (E229V, H225P and D230C) were built and simulated, and their interactions with PNLVP motif were studied...
August 12, 2016: Interdisciplinary Sciences, Computational Life Sciences
Ya-Fang Mei, Haidong Wu, Kjell Hultenby, Jim Silver
Conventional adenovirus vectors harboring E1 or E3 deletions followed by the insertion of an exogenous gene show considerably reduced virion stability. Here, we report strategies to generate complete replication-competent Ad11p(RCAd11p) vectors that overcome the above disadvantage. A GFP cassette was successfully introduced either upstream of E1A or in the E3A region. The resulting vectors showed high expression levels of the hexon and E1genes and also strongly induced the cytopathic effect in targeted cells...
October 2016: Virology
Tomáš Hošek, Eduardo O Calçada, Marcela Oliveira Nogueira, Michele Salvi, Talita Duarte Pagani, Isabella C Felli, Roberta Pierattelli
The small-DNA human adenovirus encodes one of the most versatile molecular hubs, the E1A protein. This protein is essential for productive viral infection in human cells and a vast amount of biologically relevant data are available on its interactions with host proteins. Up to now, however, no high-resolution structural and dynamic information on E1A is available despite its important biological role. Among the different spliced variants of E1A, two are expressed at high level in the early stage of infection...
September 5, 2016: Chemistry: a European Journal
Subhasree Basu, Thibaut Barnoud, Che-Pei Kung, Matthew Reiss, Maureen E Murphy
The TP53 protein is known to affect the sensitivity of tumor cells to cell death by DNA damaging agents. We recently reported that human and mouse cells containing an African-specific coding region variant of p53, Pro47Ser (hereafter S47), are impaired in the transactivation of a small subset of p53 target genes including GLS2 and SCO2, and are markedly resistant to cisplatin. Further, mice containing this variant are markedly predisposed to cancer. Together these findings suggested that cancer-affected humans with the S47 variant might not be effectively treated with cisplatin...
October 2016: Cell Cycle
Jiao Zhou, Qiu-Mei Yao, Jin-Lan Li, Yan Chang, Ting Li, Wen-Ling Han, Hong-Ping Wu, Lin-Fang Li, Qi-Jun Qian, Guo-Rui Ruan
V-set and transmembrane domain-containing 1 (VSTM1), which is downregulated in bone marrow cells from leukemia patients, may provide a diagnostic and treatment target. Here, a triple-regulated oncolytic adenovirus was constructed to carry a VSTM1 gene expression cassette, SG611-VSTM1, and contained the E1a gene with a 24-nucleotide deletion within the CR2 region under control of the human telomerase reverse transcriptase promoter, E1b gene directed by the hypoxia response element, and VSTM1 gene controlled by the cytomegalovirus promoter...
October 2016: Apoptosis: An International Journal on Programmed Cell Death
Xiangfei Yuan, Qing Zhang, Zhenzhen Li, Xiaolong Zhang, Shiqi Bao, Dongmei Fan, Yongxin Ru, Shuxu Dong, Yizhi Zhang, Yanjun Zhang, Zhou Ye, Dongsheng Xiong
Currently, it is a key challenge to remove the postsurgical residuals and metastasis of hepatocellular carcinoma (HCC). Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer; however, the difficulty remains regarding its intravenous administration. The aim of this study was to develop a targeted therapeutic system which has great potential to overcome the postsurgical residuals and metastasis of HCC. In this system, we developed a conditionally replicative adenovirus (CRAd) loaded on human umbilical cord-derived mesenchymal stem cells (HUMSCs), in which the CRAd contained an adenovirus E1A gene dual regulated by α-fetoprotein promoter and microRNA-122 target sequence...
October 10, 2016: Cancer Letters
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