Sample records for e7 oncoprotein induces

  1. Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin–proteasome system

    PubMed Central

    Jing, K; Shin, S; Jeong, S; Kim, S; Song, K-S; Park, J-H; Heo, J-Y; Seo, K-S; Park, S-K; Kweon, G-R; Wu, T; Park, J-I; Lim, K

    2014-01-01

    The oncogenic human papillomavirus (HPV) E6/E7 proteins are essential for the onset and maintenance of HPV-associated malignancies. Here, we report that activation of the cellular ubiquitin–proteasome system (UPS) by the omega-3 fatty acid, docosahexaenoic acid (DHA), leads to proteasome-mediated degradation of E6/E7 viral proteins and the induction of apoptosis in HPV-infected cancer cells. The increases in UPS activity and degradation of E6/E7 oncoproteins were associated with DHA-induced overproduction of mitochondrial reactive oxygen species (ROS). Exogenous oxidative stress and pharmacological induction of mitochondrial ROS showed effects similar to those of DHA, and inhibition of ROS production abolished UPS activation, E6/E7 viral protein destabilization, and apoptosis. These findings identify a novel role for DHA in the regulation of UPS and viral proteins, and provide evidence for the use of DHA as a mechanistically unique anticancer agent for the chemoprevention and treatment of HPV-associated tumors. PMID:25393480

  2. E7 Oncoprotein of Novel Human Papillomavirus Type 108 Lacking the E6 Gene Induces Dysplasia in Organotypic Keratinocyte Cultures ?

    PubMed Central

    Nobre, Rui Jorge; Herráez-Hernández, Elsa; Fei, Jian-Wei; Langbein, Lutz; Kaden, Sylvia; Gröne, Hermann-Josef; de Villiers, Ethel-Michele

    2009-01-01

    The genome organization of the novel human papillomavirus type 108 (HPV108), isolated from a low-grade cervical lesion, deviates from those of other HPVs in lacking an E6 gene. The three related HPV types HPV103, HPV108, and HPV101 were isolated from cervicovaginal cells taken from normal genital mucosa (HPV103) and low-grade (HPV108) and high-grade cervical (HPV101) intraepithelial neoplasia (Z. Chen, M. Schiffman, R. Herrero, R. DeSalle, and R. D. Burk, Virology 360:447-453, 2007, and this report). Their unusual genome organization, against the background of considerable phylogenetic distance from the other HPV types usually associated with lesions of the genital tract, prompted us to investigate whether HPV108 E7 per se is sufficient to induce the above-mentioned clinical lesions. Expression of HPV108 E7 in organotypic keratinocyte cultures increases proliferation and apoptosis, focal nuclear polymorphism, and polychromasia. This is associated with irregular intra- and extracellular lipid accumulation and loss of the epithelial barrier. These alterations are linked to HPV108 E7 binding to pRb and inducing its decrease, an increase in PCNA expression, and BrdU incorporation, as well as increased p53 and p21CIP1 protein levels. A delay in keratin K10 expression, increased expression of keratins K14 and K16, and loss of the corneal proteins involucrin and loricrin have also been noted. These modifications are suggestive of infection by a high-risk papillomavirus. PMID:19153227

  3. Cancerous inhibitor of protein phosphatase 2A contributes to human papillomavirus oncoprotein E7-induced cell proliferation via E2F1

    PubMed Central

    Zhang, Weifang; Chen, Hanxiang; Chen, Yan; Liu, Juan; Wang, Xiao; Yu, Xiuping; Chen, Jason J.; Zhao, Weiming

    2015-01-01

    Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in many human malignant tumors including cervical cancer. Human papillomavirus (HPV) oncoprotein E7 is the key transformation factor in cervical cancer. Our previous data showed a positive association of CIP2A and HPV-16E7 protein levels; however, how CIP2A is regulated by HPV-E7 and the roles of CIP2A in HPV-E7-mediated cell proliferation are unknown. In this study, we demonstrated that HPV-16E7 protein significantly upregulating CIP2A mRNA and protein expression depended on retinoblastoma protein pRb rather than p130. CIP2A siRNA knockdown in HPV-E7-expressing cells inhibited cell proliferation, DNA synthesis and G1/S cell cycle progression. CIP2A siRNA decreased the protein levels of cyclin-dependent kinase 1 (Cdk1), Cdk2 and their partner cyclin A2, with no change in levels of Cdk4, Cdk6 and their partner cyclin D1. The downregulation of Cdk1 and Cdk2 was independent of c-Myc; instead, E2F1 was the main target of CIP2A in this process, as overexpression of E2F1 rescued the inhibitory effects of CIP2A siRNA knockdown on cell proliferation and G1 arrest of HPV-E7-expressing cells. Our studies reveal a novel function of CIP2A in HPV-16E7-mediated cell proliferation. PMID:25650660

  4. Oncoprotein E7 from Beta Human Papillomavirus 38 Induces Formation of an Inhibitory Complex for a Subset of p53-Regulated Promoters

    PubMed Central

    Saidj, Djamel; Cros, Marie-Pierre; Hernandez-Vargas, Hector; Guarino, Francesca; Sylla, Bakary S.; Tommasino, Massimo

    2013-01-01

    Our previous studies on cutaneous beta human papillomavirus 38 (HPV38) E6 and E7 oncoproteins highlighted a novel activity of I?B kinase beta (IKK?) in the nucleus of human keratinocytes, where it phosphorylates and stabilizes ?Np73?, an antagonist of p53/p73 functions. Here, we further characterize the role of the IKK? nuclear form. We show that IKK? nuclear translocation and ?Np73? accumulation are mediated mainly by HPV38 E7 oncoprotein. Chromatin immunoprecipitation (ChIP)/Re-ChIP experiments showed that ?Np73? and IKK? are part, together with two epigenetic enzymes DNA methyltransferase 1 (DNMT1) and the enhancer of zeste homolog 2 (EZH2), of a transcriptional regulatory complex that inhibits the expression of some p53-regulated genes, such as PIG3. Recruitment to the PIG3 promoter of EZH2 and DNMT1 resulted in trimethylation of histone 3 on lysine 27 and in DNA methylation, respectively, both events associated with gene expression silencing. Decreases in the intracellular levels of HPV38 E7 or ?Np73? strongly affected the recruitment of the inhibitory transcriptional complex to the PIG3 promoter, with consequent restoration of p53-regulated gene expression. Finally, the ?Np73?/IKK?/DNMT1/EZH2 complex appears to bind a subset of p53-regulated promoters. In fact, the complex is efficiently recruited to several promoters of genes encoding proteins involved in DNA repair and apoptosis, whereas it does not influence the expression of the prosurvival factor Survivin. In summary, our data show that HPV38 via E7 protein promotes the formation of a multiprotein complex that negatively regulates the expression of several p53-regulated genes. PMID:24006445

  5. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein

    Microsoft Academic Search

    Alixandra A. Knapp; Patrick M. McManus; Katy Bockstall; Junona Moroianu

    2009-01-01

    The E7 oncoprotein of high risk human papillomavirus type 16 (HPV16) binds and inactivates the retinoblastoma (RB) family of proteins. Our previous studies suggested that HPV16 E7 enters the nucleus via a novel Ran-dependent pathway independent of the nuclear import receptors (Angeline, M., Merle, E., and Moroianu, J. (2003). The E7 oncoprotein of high-risk human papillomavirus type 16 enters the

  6. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein

    SciTech Connect

    Knapp, Alixandra A.; McManus, Patrick M.; Bockstall, Katy [Biology Department, Boston College, Higgins Hall, Room 578, 140 Commonwealth Avenue, Chestnut Hill, MA 02467 (United States); Moroianu, Junona [Biology Department, Boston College, Higgins Hall, Room 578, 140 Commonwealth Avenue, Chestnut Hill, MA 02467 (United States)], E-mail: moroianu@bc.edu

    2009-01-05

    The E7 oncoprotein of high risk human papillomavirus type 16 (HPV16) binds and inactivates the retinoblastoma (RB) family of proteins. Our previous studies suggested that HPV16 E7 enters the nucleus via a novel Ran-dependent pathway independent of the nuclear import receptors (Angeline, M., Merle, E., and Moroianu, J. (2003). The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent pathway. Virology 317(1), 13-23.). Here, analysis of the localization of specific E7 mutants revealed that the nuclear localization of E7 is independent of its interaction with pRB or of its phosphorylation by CKII. Fluorescence microscopy analysis of enhanced green fluorescent protein (EGFP) and 2xEGFP fusions with E7 and E7 domains in HeLa cells revealed that E7 contains a novel nuclear localization signal (NLS) in the N-terminal domain (aa 1-37). Interestingly, treatment of transfected HeLa cells with two specific nuclear export inhibitors, Leptomycin B and ratjadone, changed the localization of 2xEGFP-E7{sub 38-98} from cytoplasmic to mostly nuclear. These data suggest the presence of a leucine-rich nuclear export signal (NES) and a second NLS in the C-terminal domain of E7 (aa 38-98). Mutagenesis of critical amino acids in the putative NES sequence ({sub 76}IRTLEDLLM{sub 84}) changed the localization of 2xEGFP-E7{sub 38-98} from cytoplasmic to mostly nuclear suggesting that this is a functional NES. The presence of both NLSs and an NES suggests that HPV16 E7 shuttles between the cytoplasm and nucleus which is consistent with E7 having functions in both of these cell compartments.

  7. Indoleamine 2,3-dioxygenase Activity Contributes to Local Immune Suppression in the Skin Expressing Human Papillomavirus Oncoprotein E7

    PubMed Central

    Mittal, D; Kassianos, AJ; Tran, LS; Bergot, AS; Gosmann, C; Hofmann, J; Blumenthal, A; Leggatt, GR; Frazer, IH

    2013-01-01

    Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2, 3-dioxygenase (IDO) 1, an IFN-? inducible immunoregulatory molecule, is more highly expressed by langerin?ve dermal dendritic cells from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-D/L-methyl tryptophan promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN-? and iNKT cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Further, dendritic cells from K14E7 skin express higher level of IFN-? receptor (IFN-?R) than dendritic cells from control skin. K14E7 transgenic skin recruits significantly higher number of dendritic cells, independent of IFN-? and IFN-?R expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-? but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV infected skin contributes to evasion of host immunity. PMID:23652797

  8. Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells

    Microsoft Academic Search

    Anna-Marija Helt; Jens Oliver Funk; Denise A. Galloway

    2002-01-01

    The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and

  9. Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis

    PubMed Central

    Sharma, Sweta; Mandal, Paramita; Sadhukhan, Tamal; Roy Chowdhury, Rahul; Ranjan Mondal, Nidhu; Chakravarty, Biman; Chatterjee, Tanmay; Roy, Sudipta; Sengupta, Sharmila

    2015-01-01

    Human Papillomavirus (HPV) type 16 oncoprotein E7 plays a major role in cervical carcinogenesis by interacting with and functionally inactivating various host regulatory molecules. Long noncoding RNA (lncRNA) HOTAIR is one such regulator that recruits chromatin remodelling complex PRC2, creating gene silencing H3K27?me3 marks. Hence, we hypothesized that HOTAIR could be a potential target of E7, in HPV16 related cervical cancers (CaCx). We identified significant linear trend of progressive HOTAIR down-regulation through HPV negative controls, HPV16 positive non-malignants and CaCx samples. Majority of CaCx cases portrayed HOTAIR down-regulation in comparison to HPV negative controls, with corresponding up-regulation of HOTAIR target, HOXD10, and enrichment of cancer related pathways. However, a small subset had significantly higher HOTAIR expression, concomitant with high E7 expression and enrichment of metastatic pathways. Expression of HOTAIR and PRC2-complex members (EZH2 and SUZ12), showed significant positive correlation with E7 expression in CaCx cases and E7 transfected C33A cell line, suggestive of interplay between E7 and HOTAIR. Functional inactivation of HOTAIR by direct interaction with E7 could also be predicted by in silico analysis and confirmed by RNA-Immunoprecipitation. Our study depicts one of the causal mechanisms of cervical carcinogenesis by HPV16 E7, through modulation of HOTAIR expression and function. PMID:26152361

  10. Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis.

    PubMed

    Sharma, Sweta; Mandal, Paramita; Sadhukhan, Tamal; Roy Chowdhury, Rahul; Ranjan Mondal, Nidhu; Chakravarty, Biman; Chatterjee, Tanmay; Roy, Sudipta; Sengupta, Sharmila

    2015-01-01

    Human Papillomavirus (HPV) type 16 oncoprotein E7 plays a major role in cervical carcinogenesis by interacting with and functionally inactivating various host regulatory molecules. Long noncoding RNA (lncRNA) HOTAIR is one such regulator that recruits chromatin remodelling complex PRC2, creating gene silencing H3K27?me3 marks. Hence, we hypothesized that HOTAIR could be a potential target of E7, in HPV16 related cervical cancers (CaCx). We identified significant linear trend of progressive HOTAIR down-regulation through HPV negative controls, HPV16 positive non-malignants and CaCx samples. Majority of CaCx cases portrayed HOTAIR down-regulation in comparison to HPV negative controls, with corresponding up-regulation of HOTAIR target, HOXD10, and enrichment of cancer related pathways. However, a small subset had significantly higher HOTAIR expression, concomitant with high E7 expression and enrichment of metastatic pathways. Expression of HOTAIR and PRC2-complex members (EZH2 and SUZ12), showed significant positive correlation with E7 expression in CaCx cases and E7 transfected C33A cell line, suggestive of interplay between E7 and HOTAIR. Functional inactivation of HOTAIR by direct interaction with E7 could also be predicted by in silico analysis and confirmed by RNA-Immunoprecipitation. Our study depicts one of the causal mechanisms of cervical carcinogenesis by HPV16 E7, through modulation of HOTAIR expression and function. PMID:26152361

  11. The HPV16 E7 viral oncoprotein self-assembles into defined spherical oligomers.

    PubMed

    Alonso, Leonardo G; García-Alai, Maria M; Smal, Clara; Centeno, Juan M; Iacono, Rubén; Castaño, Eduardo; Gualfetti, Peter; de Prat-Gay, Gonzalo

    2004-03-30

    Despite the fact that E7 is a major transforming oncoprotein in papillomavirus, its structure and precise molecular mechanism of action remain puzzling to date. E7 proteins share sequence homology and proteasome targeting properties of tumor suppressors with adenovirus E1A and SV40 T antigen, two other paradigmatic oncoproteins from DNA tumor viruses. High-risk HPV16 E7, a nonglobular dimer with some properties of intrinsically disordered proteins, is capable of undergoing pH-dependent conformational transitions that expose hydrophobic surfaces to the solvent. We found that treatment with a chelating agent produced a protein that can readily assemble into homogeneous spherical particles with an average molecular mass of 790 kDa and a diameter of 50 nm, as determined from dynamic light scattering and electron microscopy. The protein undergoes a substantial conformational transition from coil to beta-sheet structure, with concomitant consolidation of tertiary structure as judged by circular dichroism and fluorescence. The assembly process is very slow, in agreement with a substantial energy barrier caused by structural rearrangements. The resulting particles are highly stable, cooperatively folded, and capable of binding both Congo Red and thioflavin T, reporters of repetitive beta-sheet structures similar to those found in amyloids, although no fibrillar or insoluble material was observed under our experimental conditions. PMID:15035602

  12. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth.

    PubMed Central

    Brehm, A; Nielsen, S J; Miska, E A; McCance, D J; Reid, J L; Bannister, A J; Kouzarides, T

    1999-01-01

    E7 is the main transforming protein of human papilloma virus type 16 (HPV16) which is implicated in the formation of cervical cancer. The transforming activity of E7 has been attributed to its interaction with the retinoblastoma (Rb) tumour suppressor. However, Rb binding is not sufficient for transformation by E7. Mutations within a zinc finger domain, which is dispensable for Rb binding, also abolish E7 transformation functions. Here we show that HPV16 E7 associates with histone deacetylase in vitro and in vivo, via its zinc finger domain. Using a genetic screen, we identify Mi2beta, a component of the recently identified NURD histone deacetylase complex, as a protein that binds directly to the E7 zinc finger. A zinc finger point mutant which is unable to bind Mi2beta and histone deacetylase but is still able to bind Rb fails to overcome cell cycle arrest in osteosarcoma cells. Our results suggest that the binding to a histone deacetylase complex is an important parameter for the growthpromoting activity of the human papilloma virus E7 protein. This provides the first indication that viral oncoproteins control cell proliferation by targeting deacetylation pathways. PMID:10228159

  13. Identification of the Nuclear Localization and Export Signals of High Risk HPV16 E7 Oncoprotein

    PubMed Central

    Knapp, Alixandra A.; McManus, Patrick M.; Bockstall, Katy; Moroianu, Junona

    2009-01-01

    The E7 oncoprotein of high risk human papillomavirus type 16 (HPV16) binds and inactivates the retinoblastoma (RB) family of proteins. Our previous studies suggested that HPV16 E7 enters the nucleus via a novel Ran-dependent pathway independent of the nuclear import receptors (Angeline et al., 2003). Here, analysis of the localization of specific E7 mutants revealed that the nuclear localization of E7 is independent of its interaction with pRB or of its phosphorylation by CKII. Fluorescence microscopy analysis of enhanced green fluorescent protein (EGFP) and 2xEGFP fusions with E7 and E7 domains in HeLa cells revealed that E7 contains a novel nuclear localization signal (NLS) in the N-terminal domain (aa 1-37). Interestingly, treatment of transfected HeLa cells with two specific nuclear export inhibitors, Leptomycin B and ratjadone, changed the localization of 2xEGFP-E738-98 from cytoplasmic to mostly nuclear. These data suggest the presence of a leucine-rich nuclear export signal (NES) and a second NLS in the C-terminal domain of E7 (aa 38-98). Mutagenesis of critical amino acids in the putative NES sequence (76IRTLEDLLM84) changed the localization of 2xEGFP-E738-98 from cytoplasmic to mostly nuclear suggesting that this is a functional NES. The presence of both NLSs and an NES suggests that HPV16 E7 shuttles between the cytoplasm and nucleus which is consistent with E7 having functions in both of these cell compartments. PMID:18996550

  14. Detection of human papillomavirus oncoprotein E7 in liquid-based cytology.

    PubMed

    Lidqvist, Maria; Nilsson, Olle; Holmgren, Jan; Hölters, Sebastian; Röijer, Eva; Dürst, Matthias; Fermér, Christian

    2012-02-01

    The selection and characterization of a set of mouse mAbs against high-risk human papillomavirus (HPV) E7 oncoprotein and the development of protocols for immunocytochemistry (ICC) are described here. A large number of antibodies raised towards HPV16 and 18 E7 were tested for high-risk specificity by ELISA using a panel of HPV E7 proteins. Antibodies detecting low-risk E7 were discarded, resulting in 38 high-risk HPV E7-specific antibodies. The corresponding epitopes were mapped using overlapping HPV E7 fragments displayed on phage particles. Functionality in ICC against formalin-fixed cervical cancer cell lines was demonstrated for ten mAbs; their high-risk specificity was confirmed by Western blot analysis and ICC on transiently transformed cells expressing high- or low-risk HPV E7. These mAbs were specific for one or several of the high-risk strains HPV16, 18, 31, 35 and 45. Specific E7 staining of liquid-based cytology (LBC) samples was demonstrated for seven mAbs and optimized protocols were established. The E716-41 and E718-79 mAbs demonstrated particularly strong and specific staining of cells stored in LBC fluid for at least 6 months. It is proposed that the high-risk HPV E7 staining protocols established in this study may have the potential to be included in a complementary test for the detection and identification of malignantly transformed cells, in for example atypical squamous cells of undetermined significance samples. PMID:22012460

  15. Human papillomavirus type 16 E7 oncoprotein engages but does not abrogate the mitotic spindle assembly checkpoint

    SciTech Connect

    Yu, Yueyang [Division of Infectious Diseases, Brigham and Women's Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States)] [Division of Infectious Diseases, Brigham and Women's Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States); Munger, Karl, E-mail: kmunger@rics.bwh.harvard.edu [Division of Infectious Diseases, Brigham and Women's Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States)] [Division of Infectious Diseases, Brigham and Women's Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States)

    2012-10-10

    The mitotic spindle assembly checkpoint (SAC) ensures faithful chromosome segregation during mitosis by censoring kinetochore-microtubule interactions. It is frequently rendered dysfunctional during carcinogenesis causing chromosome missegregation and genomic instability. There are conflicting reports whether the HPV16 E7 oncoprotein drives chromosomal instability by abolishing the SAC. Here we report that degradation of mitotic cyclins is impaired in cells with HPV16 E7 expression. RNAi-mediated depletion of Mad2 or BubR1 indicated the involvement of the SAC, suggesting that HPV16 E7 expression causes sustained SAC engagement. Mutational analyses revealed that HPV16 E7 sequences that are necessary for retinoblastoma tumor suppressor protein binding as well as sequences previously implicated in binding the nuclear and mitotic apparatus (NuMA) protein and in delocalizing dynein from the mitotic spindle contribute to SAC engagement. Importantly, however, HPV16 E7 does not markedly compromise the SAC response to microtubule poisons.

  16. The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent pathway

    Microsoft Academic Search

    Michael Angeline; Eric Merle; Junona Moroianu

    2003-01-01

    E7, the major transforming protein of high-risk human papillomavirus (HPV), type 16, binds and inactivates the retinoblastoma protein (pRb), and the Rb-related proteins p107 and p130. HPV16 E7 is a nuclear protein lacking a classical basic nuclear localization signal. In this study we investigated the nuclear import of HPV16 E7 oncoprotein in digitonin-permeabilized HeLa cells. HPV16 E7 nuclear import was

  17. Nuclear import of cutaneous beta genus HPV8 E7 oncoprotein is mediated by hydrophobic interactions between its zinc-binding domain and FG nucleoporins

    PubMed Central

    Onder, Zeynep; Moroianu, Junona

    2013-01-01

    We have previously discovered and characterized the nuclear import pathways for the E7 oncoproteins of mucosal alpha genus HPVs, type 16 and 11. Here we investigated the nuclear import of cutaneous beta genus HPV8 E7 protein using confocal microscopy after transfections of HeLa cells with EGFP-8E7 and mutant plasmids and nuclear import assays in digitonin-permeabilized HeLa cells. We determined that HPV8 E7 contains a nuclear localization signal (NLS) within its zinc-binding domain that mediates its nuclear import. Furthermore, we discovered that a mostly hydrophobic patch 65LRLFV69 within the zinc-binding domain is essential for the nuclear import and localization of HPV8 E7 via hydrophobic interactions with the FG nucleoporins Nup62 and Nup153. Substitution of the hydrophobic residues within the 65LRLFV69 patch to alanines, and not R66A mutation, disrupt the interactions between the 8E7 zinc-binding domain and Nup62 and Nup153 and consequently inhibit nuclear import of HPV8 E7. PMID:24418548

  18. The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells.

    PubMed

    Spardy, Nicole; Duensing, Anette; Charles, Domonique; Haines, Nathan; Nakahara, Tomomi; Lambert, Paul F; Duensing, Stefan

    2007-12-01

    Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. Episomal expression of HPV-16 oncoproteins was sufficient to activate the FA pathway. Importantly, the expression of HPV-16 E7 in FA-deficient cells led to accelerated chromosomal instability. Taken together, our findings establish the FA pathway as an early host cell response to high-risk HPV infection and may help to explain the greatly enhanced susceptibility of FA patients to squamous cell carcinogenesis at anatomic sites that are frequently infected by high-risk HPVs. PMID:17898070

  19. Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs.

    PubMed

    Uversky, Vladimir N; Roman, Ann; Oldfield, Christopher J; Dunker, A Keith

    2006-08-01

    It is recognized now that many functional proteins or their long segments are devoid of stable secondary and/or tertiary structure and exist instead as very dynamic ensembles of conformations. They are known by different names including natively unfolded, intrinsically disordered, intrinsically unstructured, rheomorphic, pliable, and different combinations thereof. Many important functions and activities have been associated with these intrinsically disordered proteins (IDPs), including molecular recognition, signaling, and regulation. It is also believed that disorder of these proteins allows function to be readily modified through phosphorylation, acetylation, ubiquitination, hydroxylation, and proteolysis. Bioinformatics analysis revealed that IDPs comprise a large fraction of different proteomes. Furthermore, it is established that the intrinsic disorder is relatively abundant among cancer-related and other disease-related proteins and IDPs play a number of key roles in oncogenesis. There are more than 100 different types of human papillomaviruses (HPVs), which are the causative agents of benign papillomas/warts, and cofactors in the development of carcinomas of the genital tract, head and neck, and epidermis. With respect to their association with cancer, HPVs are grouped into two classes, known as low (e.g., HPV-6 and HPV-11) and high-risk (e.g., HPV-16 and HPV-18) types. The entire proteome of HPV includes six nonstructural proteins [E1, E2, E4, E5, E6, and E7 (the latter two are known to function as oncoproteins in the high-risk HPVs)] and two structural proteins (L1 and L2). To understand whether intrinsic disorder plays a role in the oncogenic potential of different HPV types, we have performed a detailed bioinformatics analysis of proteomes of high-risk and low-risk HPVs with the major focus on E6 and E7 oncoproteins. The results of this analysis are consistent with the conclusion that high-risk HPVs are characterized by the increased amount of intrinsic disorder in transforming proteins E6 and E7. PMID:16889404

  20. Simultaneous human papilloma virus type 16 E7 and cdk inhibitor p21 expression induces apoptosis and cathepsin B activation.

    PubMed

    Kaznelson, Dorte Wissing; Bruun, Silas; Monrad, Astrid; Gjerløv, Simon; Birk, Jesper; Röpke, Carsten; Norrild, Bodil

    2004-03-15

    Human papillomavirus type 16 (HPV-16) is the major risk factor for development of cervical cancer. The major oncoprotein E7 enhances cell growth control. However, E7 has in some reports been shown to induce apoptosis suggesting that there is a delicate balance between cell proliferation and induction of cell death. We have used the osteosarcoma cell line U2OS cells provided with E7 and the cdk2 inhibitor p21 (cip1/waf1) under inducible control, as a model system for the analysis of E7-mediated apoptosis. Our data shows that simultaneous expression of E7 and p21 proteins induces cell death, possibly because of conflicting growth control. Interestingly, E7/p21-induced cell death is associated with the activation of a newly identified mediator of apoptosis, namely cathepsin B. Activation of the cellular caspases is undetectable in cells undergoing E7/p21-induced apoptosis. To our knowledge, this is the first time a role for cathepsin B is reported in HPV-induced apoptotic signalling. PMID:15016552

  1. Effects of the human papilloma virus HPV-16 E7 oncoprotein on glycolysis and glutaminolysis: role of pyruvate kinase type M2 and the glycolytic-enzyme complex.

    PubMed Central

    Mazurek, S; Zwerschke, W; Jansen-Dürr, P; Eigenbrodt, E

    2001-01-01

    Proliferating and tumour cells express the glycolytic isoenzyme, pyruvate kinase type M2 (M2-PK), which occurs in a highly active tetrameric form and in a dimeric form with low affinity for phosphoenolpyruvate. The switch between the two forms regulates glycolytic phosphometabolite pools and the interaction between glycolysis and glutaminolysis. In the present study, we show the effects of oncoprotein E7 of the human papilloma virus (HPV)-16 (E7)-transformation on two NIH 3T3 cell strains with different metabolic characteristics. E7-transformation of the high glycolytic NIH 3T3 cell strain led to a shift of M2-PK to the dimeric form and, in consequence, to a decrease in the cellular pyruvate kinase mass-action ratio, the glycolytic flux rate and the (ATP+GTP)/(UTP+CTP) ratio, as well as to an increase in fructose 1,6-bisphosphate (FBP) levels, glutamine consumption and cell proliferation. The low glycolytic NIH 3T3 cell strain is characterized by high pyruvate and glutamine consumption rates and by an intrinsically large amount of the dimeric form of M2-PK, which is correlated with high FBP levels, a low (ATP+GTP)/(CTP+UTP) ratio and a high proliferation rate. E7-transformation of this cell strain led to an alteration in the glycolytic-enzyme complex that correlates with an increase in pyruvate and glutamine consumption and a slight increase in the flow of glucose to lactate. The association of phosphoglyceromutase within the glycolytic-enzyme complex led to an increase of glucose and serine consumption and a disruption of the linkage between glucose consumption and glutaminolysis. In both NIH 3T3 cell lines, transformation increased glutaminolysis and the positive correlation between alanine and lactate production. PMID:11336658

  2. The EMBO Journal Vol.18 No.9 pp.24492458, 1999 The E7 oncoprotein associates with Mi2 and histone

    E-print Network

    Miska, Eric

    transformation. In contrast, `low-risk' HPVs (types 6 and 11) are associated with benign genital warts for Developmental and Cancer Biology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge) which is implicated in the formation of cervical cancer. The transforming activity of E7 has been

  3. Human Papillomavirus E7 oncoprotein transgenic skin develops an enhanced inflammatory response to 2,4-Dinitrochlorobenzene by an arginase-1 dependent mechanism

    PubMed Central

    Tran, L.S.; Bergot, A-S.; Mattarollo, S.R.

    2014-01-01

    We have shown that expression of Human Papillomavirus type 16 E7 (HPV16.E7) protein within epithelial cells, as occurs in HPV associated-premalignancy and cancers, results in local immune suppression, and a weak and ineffective immune response to E7 protein. However, a robust acute inflammatory stimulus can overcome this to enable immune elimination of HPV16.E7 transformed epithelial cells. 2,4-Dinitrochlorobenzene (DNCB) can elicit acute inflammation and has been shown to initiate the regression of HPV-associated genital warts. Although clinical use of DNCB is discouraged due to its mutagenic potential, understanding how DNCB induced acute inflammation alters local HPV16.E7 mediated-immune suppression might lead to better treatments. Here, we show that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, not seen in non-transgenic control animals. The E7 associated-inflammatory response is characterized by enhanced expression of Th2 cytokines and increased infiltration of CD11b+Gr1intF4/80+Ly6ChiLy6Glow myeloid cells, producing arginase-1. Inhibition of arginase with an arginase specific inhibitor, N(omega)-hydroxy-nor-L-arginine, ameliorates the DNCB-induced inflammatory response. Our results demonstrate that HPV16.E7 protein enhances DNCB associated-production of arginase-1 by myeloid cells and consequent inflammatory cellular infiltration of skin. PMID:24732401

  4. Roles of PI3K/Akt and c-Jun Signaling Pathways in Human Papillomavirus Type 16 Oncoprotein-Induced HIF-1?, VEGF, and IL-8 Expression and In Vitro Angiogenesis in Non-Small Cell Lung Cancer Cells

    PubMed Central

    Liu, Fei; Zhang, Peihua; Liang, Jie; Tang, Xudong

    2014-01-01

    Background and Objectives Human papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxia-inducible factor-1? (HIF-1?), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it. Methods Human NSCLC cell lines, A549 and NCI-H460, were stably transfected with pEGFP-16 E6 or E7 plasmids. Western blotting was performed to analyze the expression of HIF-1?, p-Akt, p-P70S6K, p-P85S6K, p-mTOR, p-JNK, and p-c-Jun proteins. VEGF and IL-8 protein secretion and mRNA levels were determined by ELISA and Real-time PCR, respectively. The in vitro angiogenesis was observed by human umbilical vein endothelial cells (HUVECs) tube formation assay. Co-immunoprecipitation was performed to analyze the interaction between c-Jun and HIF-1?. Results HPV-16 E6 and E7 oncoproteins promoted the activation of Akt, P70S6K, P85S6K, mTOR, JNK, and c-Jun. LY294002, a PI3K inhibitor, inhibited HPV-16 oncoprotein-induced activation of Akt, P70S6K, and P85S6K, expression of HIF-1?, VEGF, and IL-8, and in vitro angiogenesis. c-Jun knockdown by specific siRNA abolished HPV-16 oncoprotein-induced HIF-1?, VEGF, and IL-8 expression and in vitro angiogenesis. Additionally, HPV-16 oncoproteins promoted HIF-1? protein stability via blocking proteasome degradation pathway, but c-Jun knockdown abrogated this effect. Furthermore, HPV-16 oncoproteins increased the quantity of c-Jun binding to HIF-1?. Conclusions PI3K/Akt signaling pathway and c-Jun are involved in HPV-16 oncoprotein-induced HIF-1?, VEGF, and IL-8 expression and in vitro angiogenesis. Moreover, HPV-16 oncoproteins promoted HIF-1? protein stability possibly through enhancing the interaction between c-Jun and HIF-1?, thus making a contribution to angiogenesis in NSCLC cells. PMID:25058399

  5. Human papillomavirus oncoproteins and apoptosis (Review)

    PubMed Central

    JIANG, PEIYUE; YUE, YING

    2014-01-01

    The aim of this study was to review the literature and identify the association between human papillomavirus (HPV) oncoproteins and apoptosis. HPV-associated apoptosis may be primarily blocked by a number of oncoproteins, including E5, E6 and E7. E5 protein protects cells from tumor necrosis factor-associated apoptosis; the oncoprotein E6 predominantly inhibits apoptosis through the p53 pathway; and oncoprotein E7 is involved in apoptosis activation and inhibition. In addition, HPV oncoproteins are involved in activating or repressing the transcription of E6/E7. In conclusion, HPV oncoproteins, including E5, E6 and E7 protein, may interfere with apoptosis via certain regulatory principles. PMID:24348754

  6. Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7

    Microsoft Academic Search

    SONIA L. GONZALEZ; MATT STREMLAU; XI HE; JOHN R. BASILE; KARL MUNGER

    2001-01-01

    The steady-state level and metabolic half-life of retinoblastoma tumor suppressor protein pRB are decreased in cells that express high-risk human papillomavirus (HPV) E7 proteins. Here we show that pRB degradation is a direct activity of E7 and does not reflect a property of cell lines acquired during the selection process for E7 expression. An amino-terminal domain of E7 that does

  7. Berberine alters epigenetic modifications, disrupts microtubule network, and modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell HeLa: a mechanistic study including molecular docking.

    PubMed

    Saha, Santu Kumar; Khuda-Bukhsh, Anisur Rahman

    2014-12-01

    Increased evidence of chemo-resistance, toxicity and carcinogenicity necessitates search for alternative approaches for determining next generation cancer therapeutics and targets. We therefore tested the efficacy of plant alkaloid berberine on human papilloma virus (HPV) -18 positive cervical cancer cell HeLa systematically-involving certain cellular, viral and epigenetic factors. We observed disruptions of microtubule network and changes in membrane topology due to berberine influx through confocal and atomic force microscopies (AFM). We examined nuclear uptake, internucleosomal DNA damages, mitochondrial membrane potential (MMP) alterations and cell migration assays to validate possible mode of cell death events. Analytical data on interactions of berberine with pBR322 through fourier transform infrared (FTIR) and gel migration assay strengthen berberine?s biologically significant DNA binding abilities. We measured cellular uptake, DNA ploidy and DNA strand-breaks through fluorescence activated cell sorting (FACS). To elucidate epigenetic modifications, in support of DNA binding associated processes, if any, we conducted methylation-specific restriction enzyme (RE) assay, methylation specific-PCR (MSP) and expression studies of histone proteins. We also analyzed differential interactions and localization of cellular tumor suppressor p53 and viral oncoproteins HPV-18 E6-E7 through siRNA approach. We further made in-silico approaches to determine possible binding sites of berberine on histone proteins. Overall results indicated cellular uptake of berberine through cell membrane depolarization causing disruption of microtubule networks and its biological DNA binding abilities that probably contributed to epigenetic modifications. Results of modulation in p53 and viral oncoproteins HPV-18 E6-E7 by berberine further proved its potential as a promising chemotherapeutic agent in cervical cancer. PMID:25448308

  8. Nuclear import of high risk HPV16 E7 oncoprotein is mediated by its zinc-binding domain via hydrophobic interactions with Nup62

    PubMed Central

    Eberhard, Jeremy; Onder, Zeynep; Moroianu, Junona

    2013-01-01

    We previously discovered that nuclear import of high risk HPV16 E7 is mediated by a cNLS located within the zinc-binding domain via a pathway that is independent of karyopherins/importins (Angeline et al., 2003; Knapp et al., 2009). In this study we continued our characterization of the cNLS and nuclear import pathway of HPV16 E7. We find that an intact zinc-binding domain is essential for the cNLS function in mediating nuclear import of HPV16 E7. Mutagenesis of cysteine residues to alanine in each of the two CysXXCys motifs involved in zinc-binding changes the nuclear localization of the EGFP-16E7 and 2xEGFP-16E7 mutants. We further discover that a patch of hydrophobic residues, 65LRLCV69, within the zinc-binding domain of HPV16 E7 mediates its nuclear import via hydrophobic interactions with the FG domain of the central channel nucleoporin Nup62. PMID:24074597

  9. Human Papillomavirus E7 Induces Rereplication in Response to DNA Damage

    PubMed Central

    Fan, Xueli; Liu, Yingwang; Heilman, Susan A.

    2013-01-01

    Human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis. Genomic instability caused by HPV allows cells to acquire additional mutations required for malignant transformation. Genomic instability in the form of polyploidy has been demonstrated to play an important role in cervical carcinogenesis. We have recently found that HPV-16 E7 oncogene induces polyploidy in response to DNA damage; however, the mechanism is not known. Here we present evidence demonstrating that HPV-16 E7-expressing cells have an intact G2 checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G2 checkpoint and then undergo rereplication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces rereplication in human cancer cells, is upregulated in E7-expressing cells. Moreover, downregulation of Cdt1 impairs the ability of E7 to induce rereplication. These results demonstrate an important role for Cdt1 in HPV E7-induced rereplication and shed light on mechanisms by which HPV induces genomic instability. PMID:23152514

  10. Increased sensitivity of HPV-positive head and neck cancer cell lines to x-irradiation ± Cisplatin due to decreased expression of E6 and E7 oncoproteins and enhanced apoptosis.

    PubMed

    Ziemann, Frank; Arenz, Andrea; Preising, Stefanie; Wittekindt, Claus; Klussmann, Jens P; Engenhart-Cabillic, Rita; Wittig, Andrea

    2015-01-01

    Squamous cell carcinoma of the head and neck region (HNSCC), which is related to an infection with human papilloma virus (HPV), responds better to simultaneous radio-chemotherapy with Cisplatin based regimens than HPV-negative tumors. The underlying molecular mechanisms for this clinical observation are not fully understood. Therefore, the response of four HPV-positive (HPV+) (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (HPV-) (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) HNSCC cell lines to x-irradiation ± Cisplatin incubation in terms of clonogenic survival, cell cycle progression, protein expression (cyclin A2, cyclin E2, E6, E7, p53) and induction of apoptosis, was investigated. HPV+ cells were more radio- and chemosensitive and were more effectively sensitized to x-irradiation by simultaneous Cisplatin incubation than HPV- cell lines. HPV+ cell lines revealed an increased and prolonged G2/M arrest after irradiation, whereas Cisplatin induced a blockage of cells in S phase. In comparison to irradiation only, addition of Cisplatin significantly enhanced apoptosis especially in HPV+ cell lines. While irradiation alone increased the amount of HPV E6 and E7 proteins, both were down-regulated by Cisplatin incubation either alone or in combination with x-rays, which however did not increase the expression of endogenous p53. Our results demonstrate that cell cycle deregulation together with downregulation of HPV E6 and E7 proteins facilitating apoptosis after Cisplatin incubation promote the enhanced sensitivity of HPV+ HNSCC cells to simultaneous radio-chemotherapy. Combined effects of irradiation and Cisplatin appear to be relevant in mediating the enhanced therapeutic response of HPV-related HNSCC and are indicative of the benefit of combined modality approaches in future treatment optimization strategies. PMID:26045983

  11. Increased sensitivity of HPV-positive head and neck cancer cell lines to x-irradiation ± Cisplatin due to decreased expression of E6 and E7 oncoproteins and enhanced apoptosis

    PubMed Central

    Ziemann, Frank; Arenz, Andrea; Preising, Stefanie; Wittekindt, Claus; Klussmann, Jens P; Engenhart-Cabillic, Rita; Wittig, Andrea

    2015-01-01

    Squamous cell carcinoma of the head and neck region (HNSCC), which is related to an infection with human papilloma virus (HPV), responds better to simultaneous radio-chemotherapy with Cisplatin based regimens than HPV-negative tumors. The underlying molecular mechanisms for this clinical observation are not fully understood. Therefore, the response of four HPV-positive (HPV+) (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (HPV-) (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) HNSCC cell lines to x-irradiation ± Cisplatin incubation in terms of clonogenic survival, cell cycle progression, protein expression (cyclin A2, cyclin E2, E6, E7, p53) and induction of apoptosis, was investigated. HPV+ cells were more radio- and chemosensitive and were more effectively sensitized to x-irradiation by simultaneous Cisplatin incubation than HPV- cell lines. HPV+ cell lines revealed an increased and prolonged G2/M arrest after irradiation, whereas Cisplatin induced a blockage of cells in S phase. In comparison to irradiation only, addition of Cisplatin significantly enhanced apoptosis especially in HPV+ cell lines. While irradiation alone increased the amount of HPV E6 and E7 proteins, both were down-regulated by Cisplatin incubation either alone or in combination with x-rays, which however did not increase the expression of endogenous p53. Our results demonstrate that cell cycle deregulation together with downregulation of HPV E6 and E7 proteins facilitating apoptosis after Cisplatin incubation promote the enhanced sensitivity of HPV+ HNSCC cells to simultaneous radio-chemotherapy. Combined effects of irradiation and Cisplatin appear to be relevant in mediating the enhanced therapeutic response of HPV-related HNSCC and are indicative of the benefit of combined modality approaches in future treatment optimization strategies.

  12. The HPV-16 E7 oncogene sensitizes malignant cells to IFN-alpha-induced apoptosis

    SciTech Connect

    Wang, Yisong [ORNL

    2005-10-01

    Interferons (IFNs) exert antitumor effects in several human malignancies, but their mechanism of action is unclear. There is a great variability in sensitivity to IFN treatment depending on both tumor type and the individual patient. The reason for this variable sensitivity is not known. The fact that several IFN-induced anticellular effects are exerted through modulation of proto-oncogenes and tumor suppressor genes may indicate that the malignant genotype may be decisive in the cell's sensitivity to IFN. To determine if a deregulated oncogene could alter the cellular response to IFN, a mouse lymphoma cell line (J3D) was stably transfected with the viral human papillomavirus-16 (HPV-16) E7 oncogene. The E7-transfected cells and their respective mock-transfected sister clones were treated with IFN-{alpha} and examined for possible IFN-induced anticellular effects. We found that the E7-transfected clones were greatly sensitized to IFN-{alpha}-induced apoptosis compared with their mock-transfected counterparts. Induction of apoptosis in the transfected cells correlated with the ability of IFN to activate parts of the proapoptotic machinery specifically in these cells, including activation of caspases and the proapoptotic protein Bak. In summary, our data suggest that transfection of malignant cells with the E7 oncogene can sensitize them to IFN-{alpha}-induced apoptosis. This demonstrates that an oncogenic event may alter the cellular sensitivity to IFN and might also have implications for treatment of HPV related diseases with IFN.

  13. A DNA vaccine based on a shuffled E7 oncogene of the human papillomavirus type 16 (HPV 16) induces E7-specific cytotoxic T cells but lacks transforming activity

    Microsoft Academic Search

    Wolfram Osen; Tanja Peiler; Peter Öhlschläger; Sandra Caldeira; Stefan Faath; Nico Michel; Martin Müller; Massimo Tommasino; Ingrid Jochmus; Lutz Gissmann

    2001-01-01

    Vaccination with oncogene-derived DNA for anti-cancer treatment carries a risk of de-novo tumor induction triggered by the persisting recombinant DNA. We hypothesized that an oncoprotein whose primary sequence has been rearranged (‘shuffled’) to maintain all possible T cell epitopes still induces cytotoxic T cells against the authentic protein but is devoid of transforming properties. As a model antigen, we used

  14. Down-regulation of lipid raft-associated onco-proteins via cholesterol-dependent lipid raft internalization in docosahexaenoic acid-induced apoptosis.

    PubMed

    Lee, Eun Jeong; Yun, Un-Jung; Koo, Kyung Hee; Sung, Jee Young; Shim, Jaegal; Ye, Sang-Kyu; Hong, Kyeong-Man; Kim, Yong-Nyun

    2014-01-01

    Lipid rafts, plasma membrane microdomains, are important for cell survival signaling and cholesterol is a critical lipid component for lipid raft integrity and function. DHA is known to have poor affinity for cholesterol and it influences lipid rafts. Here, we investigated a mechanism underlying the anti-cancer effects of DHA using a human breast cancer cell line, MDA-MB-231. We found that DHA decreased cell surface levels of lipid rafts via their internalization, which was partially reversed by cholesterol addition. With DHA treatment, caveolin-1, a marker for rafts, and EGFR were colocalized with LAMP-1, a lysosomal marker, in a cholesterol-dependent manner, indicating that DHA induces raft fusion with lysosomes. DHA not only displaced several raft-associated onco-proteins, including EGFR, Hsp90, Akt, and Src, from the rafts but also decreased total levels of those proteins via multiple pathways, including the proteasomal and lysosomal pathways, thereby decreasing their activities. Hsp90 overexpression maintained its client proteins, EGFR and Akt, and attenuated DHA-induced cell death. In addition, overexpression of Akt or constitutively active Akt attenuated DHA-induced apoptosis. All these data indicate that the anti-proliferative effect of DHA is mediated by targeting of lipid rafts via decreasing cell surface lipid rafts by their internalization, thereby decreasing raft-associated onco-proteins via proteasomal and lysosomal pathways and decreasing Hsp90 chaperone function. PMID:24120917

  15. HPV16 E7 Reveals a Link between DNA Replication Stress, Fanconi Anemia D2 Protein, and Alternative Lengthening of Telomere-Associated Promyelocytic Leukemia Bodies

    Microsoft Academic Search

    Nicole Spardy; Anette Duensing; Elizabeth E. Hoskins; Susanne I. Wells; Stefan Duensing

    2008-01-01

    Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) in early passage primary

  16. Human papillomavirus oncoproteins: pathways to transformation

    Microsoft Academic Search

    Cary A. Moody; Laimonis A. Laimins

    2010-01-01

    An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially reported over 30 years ago, and today there is overwhelming evidence that certain subtypes of HPV are the causative agents of these malignancies. The p53 and retinoblastoma proteins are well-characterized targets of the HPV E6 and E7 oncoproteins, but recent studies have shown that the

  17. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.

    PubMed

    Martelli, Maria Paola; Gionfriddo, Ilaria; Mezzasoma, Federica; Milano, Francesca; Pierangeli, Sara; Mulas, Floriana; Pacini, Roberta; Tabarrini, Alessia; Pettirossi, Valentina; Rossi, Roberta; Vetro, Calogero; Brunetti, Lorenzo; Sportoletti, Paolo; Tiacci, Enrico; Di Raimondo, Francesco; Falini, Brunangelo

    2015-05-28

    Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (?30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics. PMID:25795919

  18. E1B and E4 Oncoproteins of Adenovirus Antagonize the Effect of Apoptosis Inducing Factor

    PubMed Central

    Turner, Roberta L.; Wilkinson, John C.; Ornelles, David A.

    2014-01-01

    Adenovirus inundates the productively infected cell with linear, double-stranded DNA and an abundance of single-stranded DNA. The cellular response to this stimulus is antagonized by the adenoviral E1B and E4 early genes. A mutant group C adenovirus that fails to express the E1B-55K and E4orf3 genes is unable to suppress the DNA-damage response. Cells infected with this double-mutant virus display significant morphological heterogeneity at late times of infection and frequently contain fragmented nuclei. Nuclear fragmentation was due to the translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. The release of AIF was dependent on active poly(ADP-ribose) polymerase-1 (PARP-1), which appeared to be activated by viral DNA replication. Nuclear fragmentation did not occur in AIF-deficient cells or in cells treated with a PARP-1 inhibitor. The E1B-55K or E4orf3 proteins independently prevented nuclear fragmentation subsequent to PARP-1 activation, possibly by altering the intracellular distribution of PAR-modified proteins. PMID:24889240

  19. Inducible short-term and stable long-term cell culture systems reveal that the PAX3-FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression

    Microsoft Academic Search

    Oana Tomescu; Shujuan J Xia; Donna Strezlecki; Jeannette L Bennicelli; Jill Ginsberg; Bruce Pawel; Frederic G Barr

    2004-01-01

    In the pediatric cancer alveolar rhabdomyosarcoma (ARMS), the 2;13 chromosomal translocation juxtaposes the PAX3 and FKHR genes to generate a chimeric transcription factor. To explore molecular pathways altered by this oncoprotein, we generated an inducible form by fusing PAX3-FKHR to a modified estrogen receptor ligand-binding domain and expressed this construct in the RD embryonal rhabdomyosarcoma cell line. This inducible system

  20. Longitudinal assessment of DNA methylation changes during HPVE6E7-induced immortalization of primary keratinocytes.

    PubMed

    Schütze, Denise M; Kooter, Jan M; Wilting, Saskia M; Meijer, Chris J L M; Quint, Wim; Snijders, Peter J F; Steenbergen, Renske D M

    2015-01-01

    High-risk human papillomavirus (hrHPV)-induced immortalization and malignant transformation are accompanied by DNA methylation of host genes. To determine when methylation is established during cell immortalization and whether it is hrHPV-type dependent, DNA methylation was studied in a large panel of HPVE6E7-immortalized keratinocyte cell lines. These cell lines displayed different growth behaviors, i.e., continuous growth versus crisis period prior to immortalization, reflecting differential immortalization capacities of the 7 HPV-types (16/18/31/33/45/66/70) studied. In this study, cells were monitored for hypermethylation of 14 host genes (APC, CADM1, CYGB, FAM19A4, hTERT, mir124-1, mir124-2, mir124-3, MAL, PHACTR3, PRDM14, RASSF1A, ROBO3, and SFRP2) at 4 different stages during immortalization. A significant increase in overall methylation levels was seen with progression through each stage of immortalization. At stage 1 (pre-immortalization), a significant increase in methylation of hTERT, mir124-2, and PRDM14 was already apparent, which continued over time. Methylation of ROBO3 was significantly increased at stage 2 (early immortal), followed by CYGB (stage 3) and FAM19A4, MAL, PHACTR3, and SFRP2 (stage 4). Methylation patterns were mostly growth behavior independent. Yet, hTERT methylation levels were significantly increased in cells that just escaped from crisis. Bisulfite sequencing of hTERT confirmed increased methylation in immortal cells compared to controls, with the transcription core and known repressor sites remaining largely unmethylated. In conclusion, HPV-induced immortalization is associated with a sequential and progressive increase in promoter methylation of a subset of genes, which is mostly independent of the viral immortalization capacity. PMID:25580631

  1. Involvement of aryl hydrocarbon receptor signaling in the development of small cell lung cancer induced by HPV E6\\/E7 oncoproteins

    Microsoft Academic Search

    Tonia Buonomo; Laura Carraresi; Mara Rossini; Rosanna Martinelli

    2011-01-01

    BACKGROUND: Lung cancers consist of four major types that and for clinical-pathological reasons are often divided into two broad categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). All major histological types of lung cancer are associated with smoking, although the association is stronger for SCLC and squamous cell carcinoma than adenocarcinoma. To date, epidemiological studies have

  2. HTLV-1 Tax Oncoprotein Inhibits the Estrogen-Induced-ER ?-Mediated BRCA1 Expression by Interaction with CBP/p300 Cofactors

    PubMed Central

    Shukrun, Meital; Jabareen, Azhar; Abou-Kandil, Ammar; Chamias, Rachel; Aboud, Mordechai; Huleihel, Mahmoud

    2014-01-01

    BRCA1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ER? receptor and regulated by certain recruited transcriptional co-activators. Interference with BRCA1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Another multifunctional protein, HTLV-1Tax oncoprotein, is widely regarded as crucial for developing adult T-cell leukemia and other clinical disorders. Tax profile reveals that it can antagonize BRCA1 expression and/or functionality. Therefore, we hypothesize that Tax expression in breast cells can sensitize them to malignant transformation by environmental carcinogens. Here we examined Tax effect on BRCA1 expression by testing its influence on E2-induced expression of BRCA1 promoter-driven luciferase reporter (BRCA1-Luc). We found that E2 strongly stimulated this reporter expression by liganding to ER?, which consequently associated with BRCA1 promoter, while ER? concomitantly recruited CBP/p300 to this complex for co-operative enhancement of BRCA1 expression. Introducing Tax into these cells strongly blocked this E2-ER?-mediated activation of BRCA1 expression. We noted, also, that Tax exerted this inhibition by binding to CBP/p300 without releasing them from their complex with ER?. Chip assay revealed that the binding of Tax to the CBP/p300-ER? complex, prevented its link to AP1 site. Interestingly, we noted that elevating the intracellular pool of CBP or p300 to excessive levels dramatically reduced the Tax-mediated inhibition of BRCA1 expression. Exploring the mechanism of this reduction revealed that the excessive co-factors were sufficient to bind separately the free Tax molecules, thus lowering their amount in the CBP/p300-ER? complex and relieving, thereby, the inhibition of BRCA1 expression. PMID:24586743

  3. Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.

    PubMed

    Scheffner, Martin; Whitaker, Noel J

    2003-02-01

    Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis. PMID:12507557

  4. The Evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death

    PubMed Central

    Kurokawa, Mineo; Mitani, Kinuko; Yamagata, Tetsuya; Takahashi, Tokiharu; Izutsu, Koji; Ogawa, Seishi; Moriguchi, Tetsuo; Nishida, Eisuke; Yazaki, Yoshio; Hirai, Hisamaru

    2000-01-01

    Evi-1 encodes a nuclear protein involved in leukemic transformation of hematopoietic cells. Evi-1 possesses two sets of zinc finger motifs separated into two domains, and its characteristics as a transcriptional regulator have been described. Here we show that Evi-1 acts as an inhibitor of c-Jun N-terminal kinase (JNK), a class of mitogen-activated protein kinases implicated in stress responses of cells. Evi-1 physically interacts with JNK, although it does not affect its phosphorylation. This interaction is required for inhibition of JNK. Evi-1 protects cells from stress-induced cell death with dependence on the ability to inhibit JNK. These results reveal a novel function of Evi-1, which provides evidence for inhibition of JNK by a nuclear oncogene product. Evi-1 blocks cell death by selectively inhibiting JNK, thereby contributing to oncogenic transformation of cells. PMID:10856240

  5. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3

    PubMed Central

    Kasprzycka, Monika; Marzec, Michal; Liu, Xiaobin; Zhang, Qian; Wasik, Mariusz A.

    2006-01-01

    The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-? and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4+ T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL. PMID:16766651

  6. Expression of LIGHT/TNFSF14 combined with vaccination against human papillomavirus Type 16 E7 induces significant tumor regression.

    PubMed

    Kanodia, Shreya; Da Silva, Diane M; Karamanukyan, Tigran; Bogaert, Lies; Fu, Yang-Xin; Kast, W Martin

    2010-05-15

    LIGHT, a ligand for the lymphotoxin-beta receptor, establishes lymphoid-like tissues inside tumor sites and recruits naïve T cells into the tumor. However, whether these infiltrating T cells are specific for tumor antigens is not known. We hypothesized that therapy with LIGHT can expand functional tumor-specific CD8(+) T cells that can be boosted using HPV16E6E7-Venezuelan equine encephalitis virus replicon particles (HPV16-VRP) and that this combined therapy can eradicate human papillomavirus 16 (HPV16)-induced tumors. Our data show that forced expression of LIGHT in tumors results in an increase in expression of IFNgamma and chemoattractant cytokines such as interleukin-1a, MIG, and macrophage inflammatory protein-2 within the tumor and that this tumor microenvironment correlates with an increase in frequency of tumor-infiltrating CD8(+) T cells. Forced expression of LIGHT also results in the expansion of functional T cells that recognize multiple tumor antigens, including HPV16 E7, and these T cells prevent the outgrowth of tumors on secondary challenge. Subsequent boosting of E7-specific T cells by vaccination with HPV16-VRP significantly increases their frequency in both the periphery and the tumor and leads to the eradication of large well-established tumors, for which either treatment alone is not successful. These data establish the safety of Ad-LIGHT as a therapeutic intervention in preclinical studies and suggest that patients with HPV16(+) tumors may benefit from combined immunotherapy with LIGHT and antigen-specific vaccination. PMID:20460520

  7. Recombinant HPV16 E7 assembled into particles induces an immune response and specific tumour protection administered without adjuvant in an animal model

    PubMed Central

    2011-01-01

    Background The HPV16 E7 protein is both a tumour-specific and a tumour-rejection antigen, the ideal target for developing therapeutic vaccines for the treatment of HPV16-associated cancer and its precursor lesions. E7, which plays a key role in virus-associated carcinogenesis, contains 98 amino acids and has two finger-type structures which bind a Zn++ ion. The ability of an Escherichia coli-produced E7-preparation, assembled into particles, to induce protective immunity against a HPV16-related tumour in the TC-1-C57BL/6 mouse tumour model, was evaluated. Methods E7 was expressed in E. coli, purified via a one-step denaturing protocol and prepared as a soluble suspension state after dialysis in native buffer. The presence in the E7 preparation of particulate forms was analysed by non-reducing SDS-PAGE and negative staining electron microscopy (EM). The Zn++ ion content was analysed by mass-spectrometry. Ten ?g of protein per mouse was administered to groups of animals, once, twice or three times without adjuvant. The E7-specific humoral response was monitored in mice sera using an E7-based ELISA while the cell-mediated immune response was analysed in mice splenocytes with lymphoproliferation and IFN-? ELISPOT assays. The E7 immunized mice were challenged with TC-1 tumour cells and the tumour growth monitored for two months. Results In western blot analysis E7 appears in multimers and high molecular mass oligomers. The EM micrographs show the protein dispersed as aggregates of different shape and size. The protein appears clustered in micro-, nano-aggregates, and structured particles. Mice immunised with this protein preparation show a significant E7-specific humoral and cell-mediated immune response of mixed Th1/Th2 type. The mice are fully protected from the tumour growth after vaccination with three E7-doses of 10 ?g without any added adjuvant. Conclusions This report shows that a particulate form of HPV16 E7 is able to induce, without adjuvant, an E7-specific tumour protection in C57BL/6 mice. The protective immunity is sustained by both humoral and cell-mediated immune responses. The E. coli-derived HPV16 E7 assembled in vitro into micro- and nanoparticles represents not only a good substrate for antigen-presenting cell uptake and processing, but also a cost-effective means for the production of a new generation of HPV subunit vaccines. PMID:21592382

  8. HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies.

    PubMed

    Spardy, Nicole; Duensing, Anette; Hoskins, Elizabeth E; Wells, Susanne I; Duensing, Stefan

    2008-12-01

    Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) in early passage primary human keratinocytes as well as HPV-negative tumor cells. This activity was found to require sequences of HPV-16 E7 involved in degradation of the retinoblastoma tumor suppressor protein as well as regions in the COOH terminus. HPV-16 E7-induced APBs contained ssDNA and several proteins that are involved in the response to DNA replication stress, most notably the Fanconi anemia D2 protein (FANCD2) as well as BRCA2 and MUS81. In line with these results, we found that FANCD2-containing APBs form in an ATR-dependent manner in HPV-16 E7-expressing cells. To directly show a role of FANCD2 in ALT, we provide evidence that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. Taken together, our results suggest a novel link between replication stress and recombination-based telomere maintenance that may play a role in HPV-16 E7-mediated extension of host cell life span and immortalization. PMID:19047177

  9. The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-?B in lymphocytes and contributes to their invasive migration

    PubMed Central

    2014-01-01

    Background The actin-bundling protein Fascin (FSCN1) is a tumor marker that is highly expressed in numerous types of cancer including lymphomas and is important for migration and metastasis of tumor cells. Fascin has also been detected in B lymphocytes that are freshly-infected with Epstein-Barr virus (EBV), however, both the inducers and the mechanisms of Fascin upregulation are still unclear. Results Here we show that the EBV-encoded oncoprotein latent membrane protein 1 (LMP1), a potent regulator of cellular signaling and transformation, is sufficient to induce both Fascin mRNA and protein in lymphocytes. Fascin expression is mainly regulated by LMP1 via the C-terminal activation region 2 (CTAR2). Block of canonical NF-?B signaling using a chemical inhibitor of I?B kinase ? (IKK?) or cotransfection of a dominant-negative inhibitor of I?B? (NFKBIA) reduced not only expression of p100, a classical target of the canonical NF-?B-pathway, but also LMP1-induced Fascin expression. Furthermore, chemical inhibition of IKK? reduced both Fascin mRNA and protein levels in EBV-transformed lymphoblastoid cell lines, indicating that canonical NF-?B signaling is required for LMP1-mediated regulation of Fascin both in transfected and transformed lymphocytes. Beyond that, chemical inhibition of IKK? significantly reduced invasive migration of EBV-transformed lymphoblastoid cells through extracellular matrix. Transient transfection experiments revealed that Fascin contributed to LMP1-mediated enhancement of invasive migration through extracellular matrix. While LMP1 enhanced the number of invaded cells, functional knockdown of Fascin by two different small hairpin RNAs resulted in significant reduction of invaded, non-attached cells. Conclusions Thus, our data show that LMP1-mediated upregulation of Fascin depends on NF-?B and both NF-?B and Fascin contribute to invasive migration of LMP1-expressing lymphocytes. PMID:25105941

  10. Identification of unusual E6 and E7 proteins within avian papillomaviruses: cellular localization, biophysical characterization, and phylogenetic analysis.

    PubMed

    Van Doorslaer, Koenraad; Sidi, Abdellahi Ould M'hamed Ould; Zanier, Katia; Rybin, Vladimir; Deryckère, François; Rector, Annabel; Burk, Robert D; Lienau, E Kurt; van Ranst, Marc; Travé, Gilles

    2009-09-01

    Papillomaviruses (PVs) are a large family of small DNA viruses infecting mammals, reptiles, and birds. PV infection induces cell proliferation that may lead to the formation of orogenital or skin tumors. PV-induced cell proliferation has been related mainly to the expression of two small oncoproteins, E6 and E7. In mammalian PVs, E6 contains two 70-residue zinc-binding repeats, whereas E7 consists of a natively unfolded N-terminal region followed by a zinc-binding domain which folds as an obligate homodimer. Here, we show that both the novel francolin bird PV Francolinus leucoscepus PV type 1 (FlPV-1) and the chaffinch bird PV Fringilla coelebs PV contain unusual E6 and E7 proteins. The avian E7 proteins contain an extended unfolded N terminus and a zinc-binding domain of reduced size, whereas the avian E6 proteins consist of a single zinc-binding domain. A comparable single-domain E6 protein may have existed in a common ancestor of mammalian and avian PVs. Mammalian E6 C-terminal domains are phylogenetically related to those of single-domain avian E6, whereas mammalian E6 N-terminal domains seem to have emerged by duplication and subsequently diverged from the original ancestral domain. In avian and mammalian cells, both FlPV-1 E6 and FlPV-1 E7 were evenly expressed in the cytoplasm and the nucleus. Finally, samples of full-length FlPV-1 E6 and the FlPV-1 E7 C-terminal zinc-binding domain were prepared for biophysical analysis. Both constructs were highly soluble and well folded, according to nuclear magnetic resonance spectroscopy measurements. PMID:19553340

  11. Identification of Unusual E6 and E7 Proteins within Avian Papillomaviruses: Cellular Localization, Biophysical Characterization, and Phylogenetic Analysis? §

    PubMed Central

    Van Doorslaer, Koenraad; Ould M'hamed Ould Sidi, Abdellahi; Zanier, Katia; Rybin, Vladimir; Deryckère, François; Rector, Annabel; Burk, Robert D.; Lienau, E. Kurt; van Ranst, Marc; Travé, Gilles

    2009-01-01

    Papillomaviruses (PVs) are a large family of small DNA viruses infecting mammals, reptiles, and birds. PV infection induces cell proliferation that may lead to the formation of orogenital or skin tumors. PV-induced cell proliferation has been related mainly to the expression of two small oncoproteins, E6 and E7. In mammalian PVs, E6 contains two 70-residue zinc-binding repeats, whereas E7 consists of a natively unfolded N-terminal region followed by a zinc-binding domain which folds as an obligate homodimer. Here, we show that both the novel francolin bird PV Francolinus leucoscepus PV type 1 (FlPV-1) and the chaffinch bird PV Fringilla coelebs PV contain unusual E6 and E7 proteins. The avian E7 proteins contain an extended unfolded N terminus and a zinc-binding domain of reduced size, whereas the avian E6 proteins consist of a single zinc-binding domain. A comparable single-domain E6 protein may have existed in a common ancestor of mammalian and avian PVs. Mammalian E6 C-terminal domains are phylogenetically related to those of single-domain avian E6, whereas mammalian E6 N-terminal domains seem to have emerged by duplication and subsequently diverged from the original ancestral domain. In avian and mammalian cells, both FlPV-1 E6 and FlPV-1 E7 were evenly expressed in the cytoplasm and the nucleus. Finally, samples of full-length FlPV-1 E6 and the FlPV-1 E7 C-terminal zinc-binding domain were prepared for biophysical analysis. Both constructs were highly soluble and well folded, according to nuclear magnetic resonance spectroscopy measurements. PMID:19553340

  12. A20/TNFAIP3 inhibits NF-?B activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein.

    PubMed

    Sakakibara, S; Espigol-Frigole, G; Gasperini, P; Uldrick, T S; Yarchoan, R; Tosato, G

    2013-03-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP (viral Flice-inhibitory protein) induces transcription of numerous genes through NF-?B activation, including pro-inflammatory cytokines, which contribute to the pathogenesis of Kaposi's sarcoma (KS). In this study, we report that KSHV vFLIP induces the expression of the NF-?B regulatory proteins A20, ABIN-1 and ABIN-3 (A20-binding NF-?B inhibitors) in primary human endothelial cells, and that KS spindle cells express A20 in KS tissue. In reporter assays, A20 strongly impaired vFLIP-induced NF-?B activation in 293T cells, but ABIN-1 and ABIN-3 did not. Mutational analysis established that the C-terminal domain (residues 427-790) is critical for A20 modulation of NF-?B, but the ubiquitin-editing OTU (ovarian tumor) domain is not. In functional assays, A20 inhibited vFLIP-induced expression of the chemokine IP-10, reduced vFLIP-induced cell proliferation and increased IKK1 protein levels. Thus, we demonstrate that A20 negatively regulates NF-?B activation directly induced by KSHV vFLIP. By attenuating excessive and prolonged vFLIP-induced NF-?B activation that could be harmful to KSHV-infected cells, A20 likely has an important role in the pathogenesis of KSHV-associated diseases, in which vFLIP is expressed. PMID:22525270

  13. Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-?B activation.

    PubMed

    Graham, Ciaren; Matta, Hittu; Yang, Yanqiang; Yi, Han; Suo, Yulan; Tolani, Bhairavi; Chaudhary, Preet M

    2013-02-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease (MCD). We have characterized the role of KSHV-encoded viral FLICE inhibitory protein (vFLIP) K13 in the modulation of anti-IgM-induced growth arrest and apoptosis in B cells. We demonstrate that K13 protects WEHI 231, an immature B-cell line, against anti-IgM-induced growth arrest and apoptosis. The protective effect of K13 was associated with the activation of the NF-?B pathway and was deficient in a mutant K13 with three alanine substitutions at positions 58 to 60 (K13-58AAA) and a structural homolog, vFLIP E8, both of which lack NF-?B activity. K13 upregulated the expression of NF-?B subunit RelB and blocked the anti-IgM-induced decline in c-Myc and rise in p27(Kip1) that have been associated with growth arrest and apoptosis. K13 also upregulated the expression of Mcl-1, an antiapoptotic member of the Bcl2 family. Finally, K13 protected the mature B-cell line Ramos against anti-IgM-induced apoptosis through NF-?B activation. Inhibition of anti-IgM-induced apoptosis by K13 may contribute to the development of KSHV-associated lymphoproliferative disorders. PMID:23236068

  14. Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells.

    PubMed

    Wang, Xuening; Studzinski, George P

    2011-05-01

    Metabolites and derivatives of vitamin D are well-known inducers of monocytic differentiation, but the mechanistic basis for their action is not fully elucidated. Here we show that the product of protooncogene Cot1 represses the monocytic phenotype in human acute myeloid leukemia (AML) cells induced to differentiate by 1,25-dihydroxyvitamin D(3) (1,25D), even though the expression of cellular Cot1 increases early in the process of 1,25D-induced differentiation. Interestingly, the expression of the two members of the Kinase Suppressor of Ras (KSR) family of molecular scaffolds, known to be positive regulators of Ras signaling and of 1,25D-induced differentiation, increases in parallel with Cot1 in 1,25D-treated cells. However, KSR1/2 are negatively regulated by Cot1, as determined by transfection of siCot1, and confirmed by a reverse effect of ectopic expression of Cot1. The effect of Cot1 in AML cells appears to be cell-type specific, as previous reports in other cell types found KSR-2 to be a negative regulator of Cot1, a reverse relationship. Also in contrast to findings in other cells, in AML cells Cot1 exerts negative control on the MAP kinase pathways, since siCot1 increases the levels of activated Raf1, p90RSK, JNK1, c-jun, and p38, though not of MEK/ERK. These findings have implications for therapy of AML, since in AML cells active MAPKs hasten cell differentiation, and specific pharmacological inhibitors of Cot1 kinase activity have recently became available, thus making Cot1 a "druggable" target. PMID:20945381

  15. Oncoprotein Cot1 Represses Kinase Suppressors of Ras1/2 and 1,25-Dihydroxyvitamin D3-Induced Differentiation of Human Acute Myeloid Leukemia Cells

    PubMed Central

    WANG, XUENING; STUDZINSKI, GEORGE P.

    2012-01-01

    Metabolites and derivatives of vitamin D are well-known inducers of monocytic differentiation, but the mechanistic basis for their action is not fully elucidated. Here we show that the product of protooncogene Cot1 represses the monocytic phenotype in human acute myeloid leukemia (AML) cells induced to differentiate by 1,25-dihydroxyvitamin D3 (1,25D), even though the expression of cellular Cot1 increases early in the process of 1,25D-induced differentiation. Interestingly, the expression of the two members of the Kinase Suppressor of Ras (KSR) family of molecular scaffolds, known to be positive regulators of Ras signaling and of 1,25D-induced differentiation, increases in parallel with Cot1 in 1,25D-treated cells. However, KSR1/2 are negatively regulated by Cot1, as determined by transfection of siCot1, and confirmed by a reverse effect of ectopic expression of Cot1. The effect of Cot1 in AML cells appears to be cell-type specific, as previous reports in other cell types found KSR-2 to be a negative regulator of Cot1, a reverse relationship. Also in contrast to findings in other cells, in AML cells Cot1 exerts negative control on the MAP kinase pathways, since siCot1 increases the levels of activated Raf1, p90RSK, JNK1, c-jun, and p38, though not of MEK/ERK. These findings have implications for therapy of AML, since in AML cells active MAPKs hasten cell differentiation, and specific pharmacological inhibitors of Cot1 kinase activity have recently became available, thus making Cot1 a “druggable” target. PMID:20945381

  16. The Gfi-1 Proto-Oncoprotein Contains a Novel Transcriptional Repressor Domain, SNAG, and Inhibits G1Arrest Induced by Interleukin2 Withdrawal

    Microsoft Academic Search

    H. LEIGHTON GRIMES; TUNG O. CHAN; PATRICK A. ZWEIDLER-MCKAY; BETTY TONG; ANDPHILIP N. TSICHLIS

    1996-01-01

    TheGfi-1 proto-oncogene is activated by provirus insertion in T-cell lymphoma lines selected for interleu- kin-2 (IL-2) independence in culture and in primary retrovirus-induced thymomas and encodes a nuclear, sequence-specific DNA-binding protein. Here we show that Gfi-1 is a position- and orientation-independent active transcriptional repressor, whose activity depends on a 20-amino-acid N-terminal repressor domain, coincident with a nuclear localization motif. The

  17. Cellular Immunity Induced by a Novel HPV-18 DNA Vaccine Encoding an E6/E7 Fusion Consensus Protein in Mice and Rhesus Macaques

    PubMed Central

    Yan, Jian; Harris, Kristina; Khan, Amir S.; Draghia-Akli, Ruxandra; Sewell, Duane; Weiner, David B.

    2015-01-01

    Human papilloma-virus (HPV) infection is the major cause of cervical cancer. HPV 18 is the most prevalence high-risk HPV after type 16 that accounts for the largest number of cervical cancer cases worldwide. Currently, although prophylactic vaccines have been developed, there is still an urgent need to develop therapeutic HPV vaccines for targeting tumors post infection. In this study, we utilize a novel multi-phase strategy for HPV 18 antigen development with the goal of increasing anti-HPV18 cellular immunity. Our data show that this construct can induce strong cellular immune responses against HPV 18 E6 and E7 antigens in a murine model. Moreover, when applied to Rhesus monkeys, this construct is also able to elicit cellular immunity. These data suggest such DNA immunogens are candidates for further study in the eventual context of immunotherapy for HPV-associated cancers. PMID:18455277

  18. Human telomerase reverse transcriptase regulates vascular endothelial growth factor expression via human papillomavirus oncogene E7 in HPV-18-positive cervical cancer cells.

    PubMed

    Li, Fang; Cui, Jinquan

    2015-07-01

    Human papillomavirus (HPV) infection induces chronic and precancerous lesions and results in invasive cervical cancer. Human telomerase as well as inflammatory and angiogenic factors such as telomerase reverse transcriptase (hTERT) or vascular endothelial growth factor (VEGF) could play a role in regulating HPV-induced cervical cancer. This study investigated underlying molecular events in HPV-induced HPV-positive cervical cancer through hTERT and VEGF in vitro. Expressions of hTERT, a rate-limiting subunit of telomerase, and VEGF mRNA and proteins were, respectively, assessed by qRT-PCR, ELISA, and TRAP-ELISA in HPV-positive tissue samples and cervical cancer cell lines. To assess hTERT and VEGF secretion, hTERT overexpression and knockdown were conducted in HPV-18-positive Hela cells by hTERT cDNA and shRNA transfection, respectively. Then, the effect of HPV E6 and E7 on VEGF expressions was assessed in HPV-negative cervical cancer cells. Data have shown that VEGF expression levels are associated with hTERT expressions and telomerase activity in HPV-positive cervical cancer tissues and cells. Knockdown of hTERT expression down-regulated VEGF expressions, whereas overexpression of hTERT up-regulated VEGF expressions in HPV-18-positive Hela cells. Furthermore, HPV E7 oncoprotein was necessary for hTERT to up-regulate VEGF expressions in HPV-negative cervical cancer cells. Data from this current study indicate that HPV oncoproteins up-regulated hTERT and telomerase activity and in turn promoted VEGF expressions, which could be a key mechanism for HPV-induced cervical cancer development and progression. PMID:26067630

  19. Bcr: a negative regulator of the Bcr-Abl oncoprotein.

    PubMed

    Wu, Y; Ma, G; Lu, D; Lin, F; Xu, H J; Liu, J; Arlinghaus, R B

    1999-08-01

    Chronic myelogenous leukemia is typically characterized by the presence of the Philadelphia chromosome (Ph) in which 5' portions of the BCR gene are fused to a large portion of the ABL gene. Our studies and those of others indicate that Bcr sequences within the Bcr-Abl oncoprotein are critically involved in activating the Abl tyrosine kinase and actively participate in the oncogenic response, which is generated by the Bcr-Abl oncoprotein. We investigated the role of the Bcr protein in the oncogenic effects of Bcr-Abl. Reduction of the level of the Bcr protein by incubating cells with a 3' BCR anti-sense oligodeoxynucleotide increased the growth rate and survival of hematopoietic cell lines expressing Bcr-Abl. Also, enforced expression of Bcr in Bcr-Abl cell lines strongly reduced transformation efficiency. Induction of Bcr expression drastically reduced the phosphotyrosine content of Bcr-Abl in Rat-1 fibroblasts transformed by P185 BCR-ABL and in hematopoietic cells expressing P210 Bcr-Abl within days following induction of Bcr. Rat-1/P185 cells maintained for three weeks after Bcr induction had dramatically reduced amounts of phosphotyrosine proteins compared to cells in which Bcr expression was repressed by the addition of Tet. In contrast Bcr expression did not decrease the phosphotyrosine content of either v-Src or activated Neu tyrosine kinase. Importantly, the phosphotyrosine content of total P160 BCR (induced plus endogenous) was strongly reduced by inducing expression of Bcr, indicating that the induced Bcr protein was not a target of the tyrosine kinase activity of Bcr-Abl but instead functioned as an inhibitor of Bcr-Abl. These results show that the Bcr protein can function as a negative regulator of Bcr-Abl, but that the inhibitory effects of Bcr are dependent on achieving an elevated level of Bcr expression relative to Bcr-Abl. PMID:10442632

  20. The biological properties of E6 and E7 oncoproteins from human papillomaviruses

    Microsoft Academic Search

    Raffaella Ghittoni; Rosita Accardi; Uzma Hasan; Tarik Gheit; Bakary Sylla; Massimo Tommasino

    2010-01-01

    More than 100 different human papillomavirus (HPV) types have been isolated so far, and they can be sub-grouped in cutaneous\\u000a or mucosal according to their ability to infect the skin or the mucosa of the genital or upper-respiratory tracts. A sub-group\\u000a of human mucosal HPVs, referred to as high-risk HPV types, is responsible for approximately 5% of all human cancers,

  1. Histone demethylase JARID1B promotes cell proliferation but is downregulated by N-Myc oncoprotein.

    PubMed

    Zhang, Lihong; Sokolowski, Nicolas; Atmadibrata, Bernard; Liu, Tao

    2014-04-01

    Myc oncoproteins induce tumor initiation and promote tumor progression by modulating gene transcription. We have previously shown that N-Myc represses gene transcription by recruiting histone deacetylases to Sp1-binding site-enriched regions of target gene promoters. The histone demethylase JARID1B plays a dual role in cancer. In the present study, we examined published microarray gene expression datasets and found that JARID1B was commonly repressed by Myc oncoproteins and histone deacetylases in cancer cell lines of various organ origins. Chromatin immunoprecipitation assays demonstrated that N-Myc repressed JARID1B expression by direct binding to the Sp1-binding site-enriched region of the JARID1B gene promoter, and cell proliferation assays showed that transcriptional repression of JARID1B reduced neuroblastoma cell proliferation. Our findings suggest that Myc-mediated transcriptional repression of JARID1B counterintuitively inhibits Myc-regulated cell proliferation and potentially tumorigenesis. PMID:24481781

  2. Structural Insights into a Wildtype Domain of the Oncoprotein E6 and Its Interaction with a PDZ Domain

    PubMed Central

    Mischo, André; Ohlenschläger, Oliver; Hortschansky, Peter; Ramachandran, Ramadurai; Görlach, Matthias

    2013-01-01

    The high-risk human papilloma virus (HPV) oncoproteins E6 and E7 interact with key cellular regulators and are etiological agents for tumorigenesis and tumor maintenance in cervical cancer and other malignant conditions. E6 induces degradation of the tumor suppressor p53, activates telomerase and deregulates cell polarity. Analysis of E6 derived from a number of high risk HPV finally yielded the first structure of a wild-type HPV E6 domain (PDB 2M3L) representing the second zinc-binding domain of HPV 51 E6 (termed 51Z2) determined by NMR spectroscopy. The 51Z2 structure provides clues about HPV-type specific structural differences between E6 proteins. The observed temperature sensitivity of the well-folded wild-type E6 domain implies a significant malleability of the oncoprotein in vivo. Hence, the structural differences between individual E6 and their malleability appear, together with HPV type-specific surface exposed side-chains, to provide the structural basis for the different interaction networks reported for individual E6 proteins. Furthermore, the interaction of 51Z2 with a PDZ domain of hDlg was analyzed. Human Dlg constitutes a prototypic representative of the large family of PDZ proteins regulating cell polarity, which are common targets of high-risk HPV E6. Nine C-terminal residues of 51Z2 interact with the second PDZ domain of hDlg2. Surface plasmon resonance in conjunction with the NMR spectroscopy derived complex structure (PDB 2M3M) indicate that E6 residues N-terminal to the canonical PDZ-BM of E6 significantly contribute to this interaction and increase affinity. The structure of the complex reveals how residues outside of the classical PDZ-BM enhance the affinity of E6 towards PDZ domains. Such mechanism facilitates successful competition of E6 with cellular PDZ-binding proteins and may apply to PDZ-binding proteins of other viruses as well. PMID:23638119

  3. Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

    Microsoft Academic Search

    Katja Nilges; Hanni Hohn; Henryk Pilch; Claudia Neukirch; Kirsten Freitag; P. J. Talbot; Markus J. Maeurer

    2003-01-01

    Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity repre- sents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral

  4. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells.

    PubMed

    Singh, Mayank; Singh, Neeta

    2011-01-01

    Cervical cancer is the most common cancer in Indian females and is associated with infection with high-risk Human papilloma viruses (HPVs) which encode viral oncoprotein E6 and E7. Estradiol has been established as a risk factor for cervical cancer and has been shown to play a synergistic role with viral oncoproteins. Curcumin (Diferuloyl methane), a chemopreventive agent, is a natural compound extracted from Curcuma longa that allows suppression and retardation of carcinogenesis in many types of cancer and is currently being tested in various human clinical trials as it has been found to be well tolerated at higher doses with a relatively well established safety profile. The objective of this study was to test the effect of curcumin on HPV-positive and negative cervical cancer cell lines HeLa, SiHa, CaSki, and C33A pretreated with estradiol. It was found that HPV-positive cells pretreated with estradiol show reduced apoptosis as compared to curcumin by itself. However, curcumin was able to counteract the proliferative response of estradiol, and induce apoptosis. There was no difference in percentage apoptosis as compared to estradiol pretreatment in HPV-negative cell line C33A. Molecular studies showed elevation of Telomerase, viral oncoproteins E6 and E7, PCNA, p16, Cyclin D1 in HPV-positive cell lines on treatment with estradiol but after treatment with curcumin the level of E7, PCNA, and Cyclin D1 was reduced but the level of E6, Telomerase, and p16 was unaltered. Furthermore, estradiol-pretreated HPV-negative cell line C33A showed reduction in level of Telomerase, PCNA, p16, and activation of both p53 and p73 tumor suppressor proteins, thus, demonstrating the importance of E6 in estradiol-mediated protective effect. PMID:20941532

  5. Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor effects against cervicovaginal tumors

    PubMed Central

    Sun, Y; Peng, S; Qiu, J; Miao, J; Yang, B; Jeang, J; Hung, C-F; Wu, T-C

    2015-01-01

    Therapeutic human papillomavirus (HPV) vaccines have the potential to inhibit the progression of an established HPV infection to precancer and cancer lesions by targeting HPV oncoproteins. We have previously developed a therapeutic DNA vaccine encoding calreticulin (CRT) linked to E7, CRT/E7 DNA vaccine, for use in the treatment of HPV-associated lesions. Since the transfection efficiency of DNA vaccines administered in vivo is typically low, we examined the use of electroporation as well as different routes of administration to enhance antigen-specific tumor control. We tested the effects of the CRT/E7 DNA vaccine administered intramuscularly or intravaginally, with or without electroporation, on the generation of CD8+ T-cell immunity and therapeutic antitumor effects in HPV16 E7-expressing cervicovaginal tumor-bearing mice. We found that intravaginal vaccination of CRT/E7 DNA followed by electroporation-induced potent E7-specific CD8+ T-cell responses in the cervicovaginal tract, compared with intramuscular injection followed by electroporation. Furthermore, tumor-bearing mice vaccinated intravaginally followed by electroporation had an enhanced survival, antitumor effects and local production of IFN-?+CD8+ T cells compared with those vaccinated intramuscularly with electroporation. Thus, we show that intravaginal CRT/E7 DNA vaccination followed by electroporation generates the most potent therapeutic antitumor effects against an orthotopic E7-expressing tumor model. The current study will have significant clinical implications once a clinically applicable electroporation device for intravaginal use becomes available. PMID:25786869

  6. New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer

    Microsoft Academic Search

    K Yamato; T Yamada; M Kizaki; K Ui-Tei; Y Natori; M Fujino; T Nishihara; Y Ikeda; Y Nasu; K Saigo; M Yoshinouchi

    2008-01-01

    Persistent infection by high-risk types of human papillomaviruses (HPV) is a necessary cause of cervical cancer, with HPV16 the most prevalent, accounting for more than 50% of reported cases. The virus encodes the E6 and E7 oncoproteins, whose expression is essential for maintenance of the malignant phenotype. To select efficacious siRNAs applicable to RNAi therapy for patients with HPV16+ cervical

  7. The multiple cellular functions of the oncoprotein Golgi phosphoprotein 3

    PubMed Central

    Belloni, Giorgio; Colotti, Gianni; Giansanti, Maria Grazia

    2015-01-01

    The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein, a component of Trans-Golgi Network (TGN), has been defined as a “first-in-class Golgi oncoprotein” and characterized as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is commonly amplified in several solid tumors. Furthermore this protein has been associated with poor prognosis in many cancers. Highly conserved from yeast to humans, GOLPH3 provides an essential function in vesicle trafficking and Golgi structure. Recent data have also implicated this oncoprotein in regulation of cytokinesis, modulation of mitochondrial mass and cellular response to DNA damage. A minute dissection of the molecular pathways that require GOLPH3 protein will be helpful to develop new therapeutic cancer strategies. PMID:25691054

  8. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins

    Microsoft Academic Search

    Masahiro Aoki; Hao Jiang; Peter K. Vogt

    2004-01-01

    The P3k oncoprotein [homolog of the catalytic subunit p110 of class 1A phosphoinositide 3-kinase (PI3K)] and its downstream effector Akt induce oncogenic transformation in cultures of chicken embryo fibroblasts (CEF). The winged helix transcription factor FoxO1 is a growth-attenuating and proapoptotic protein and serves as a substrate of Akt. Here we show that FoxO1 expression is constitutively suppressed in CEF

  9. Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes in women with cervical neoplasia.

    PubMed

    Bontkes, H J; de Gruijl, T D; van den Muysenberg, A J; Verheijen, R H; Stukart, M J; Meijer, C J; Scheper, R J; Stacey, S N; Duggan-Keen, M F; Stern, P L; Man, S; Borysiewicz, L K; Walboomers, J M

    2000-10-01

    Infection with oncogenic human papillomavirus (HPV) types is associated with the development of cervical neoplasia (CIN). The E6 and E7 oncoproteins are constitutively expressed in these lesions and are therefore putative targets for the immune response against HPV. The relation between HPV 16-specific memory cytotoxic T-cell precursor (mCTLp) activity to both oncoproteins and the natural course of cervical dysplasia was analyzed in 38 patients participating in a nonintervention cohort study of women with CIN and 11 HPV 16-positive cervical carcinoma patients. In a cross-sectional study at the end of follow-up prior to biopsy, 8 of 20 patients with a persistent HPV 16 infection had specific mCTLp against at least one of the two oncoproteins. By contrast, no specific mCTLp activity was detected in 11 HPV-negative patients or in 7 patients who had cleared an HPV 16 infection at the end of follow-up. However, 5 of 11 cervical carcinoma patients showed mCTLp activity against the E7 protein only. This study demonstrates that HPV 16 oncogene-specific mCTLp are present in women with HPV 16-positive CIN prior to any intervention. Since HPV-specific mCTLp were detected predominantly in women with high-grade lesions or invasive cervical carcinoma and not in women who cleared the virus, the role of naturally occurring mCTLp in the protection against HPV-associated cervical neoplasia remains to be established. PMID:10962445

  10. The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax

    PubMed Central

    Fryrear, Kimberly A.; Guo, Xin

    2012-01-01

    The Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-?B–mediated and decreased cAMP Response Element-Binding (CREB)–mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage–induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes. PMID:22106342

  11. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells

    Microsoft Academic Search

    Mayank SinghNeeta Singh; Neeta Singh

    2011-01-01

    Cervical cancer is the most common cancer in Indian females and is associated with infection with high-risk Human papilloma\\u000a viruses (HPVs) which encode viral oncoprotein E6 and E7. Estradiol has been established as a risk factor for cervical cancer\\u000a and has been shown to play a synergistic role with viral oncoproteins. Curcumin (Diferuloyl methane), a chemopreventive agent,\\u000a is a natural

  12. Transient expression of HPV16 E7 peptide (aa 44–60) and HPV16 L2 peptide (aa 108–120) on chimeric potyvirus-like particles using Potato virus X-based vector

    Microsoft Academic Search

    Noemi ?e?ovská; Hana Hoffmeisterová; Tamara Pe?enková; Tomáš Moravec; Helena Synková; Helena Plchová; Ji?í Velemínský

    2008-01-01

    The optimized expression of recombinant Potato virus A coat protein (ACP) carrying two different epitopes from Human papillomavirus type 16 (HPV16) was developed. Epitope derived from minor capsid protein L2 was expressed as N-terminal fusion with ACP while an epitope derived from E7 oncoprotein was fused to its C-terminus. The construct was cloned into Potato X potexvirus (PVX) based vector

  13. The oncoprotein HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation.

    PubMed

    Li, Leilei; Liu, Bowen; Zhang, Xiaodong; Ye, Lihong

    2015-03-13

    We have documented that the oncoprotein hepatitis B X-interacting protein (HBXIP) is able to promote migration of breast cancer cells. A subset of acetylated microtubules that accumulates in the cell leading edge is necessary for cell polarization and directional migration. In this study, we explored the hypothesis that HBXIP contributes to migration of breast cancer cells by supporting microtubule acetylation in breast cancer cells. We found that HBXIP could induce acetylated microtubules accumulating into the leading protrusion in wound-induced directional migration in breast cancer cells by immunofluorescence staining analysis. Interestingly, HBXIP was able to increase the acetylation of ?-tubulin in the cells by immunofluorescence staining and Western blot analysis. Furthermore, we observed that acetyltransferase GCN5 was involved in the event that HBXIP induced increase of acetylated microtubules and their expansion in protrusions in breast cancer cells by Western blot analysis and immunofluorescence staining. Moreover, GCN5 was required for the HBXIP-enhanced migration of breast cancer cells by wound healing assay. Thus, we conclude that HBXIP promotes the migration of breast cancer cells through modulating microtubule acetylation mediated by GCN5. Therapeutically, HBXIP may serve as a novel target in breast cancer. PMID:25686500

  14. Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo

    PubMed Central

    Jung, Hun Soon; Rajasekaran, Nirmal; Song, Sang Yong; Kim, Young Deug; Hong, Sungyoul; Choi, Hyuck Jae; Kim, Young Seok; Choi, Jong-Sun; Choi, Yoon-La; Shin, Young Kee

    2015-01-01

    The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV-derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated ?-galactosidase (SA-?-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas. PMID:26035754

  15. E7 properties of mucosal human papillomavirus types 26, 53 and 66 correlate with their intermediate risk for cervical cancer development

    SciTech Connect

    Mansour, Mariam; Touka, Majid; Hasan, Uzma; Bellopede, Angelica; Smet, Anouk; Accardi, Rosita; Gabet, Anne-Sophie; Sylla, Bakary S. [Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69008 Lyon (France); Tommasino, Massimo [Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69008 Lyon (France)], E-mail: tommasino@iarc.fr

    2007-10-10

    Epidemiological studies have demonstrated that 15 different mucosal human papillomavirus (HPV) types of the genus alpha of the HPV phylogetic tree are classified as high risk for cervical cancer development. Three additional HPV types of the same genus, HPV26, 53 and 66, are classified as probable high-risk types. In this study, we have characterized the biological properties of the E7 oncoproteins from these three HPV types. All of the corresponding E7 proteins were able to associate with retinoblastoma protein (pRb) and up-regulated the expression of several positive cell cycle regulators, i.e. CDK2, cyclin A and cylin E. However, HPV26 E7 appears to be more efficient than HPV53 and 66 E7 in up-regulating the transcription of cyclin A. Unlike E7 from the high-risk type HPV16 protein, HPV26, 53 and 66 did not efficiently promote pRb degradation. In addition, E7 from these viruses was able to promote proliferation of primary human keratinocytes and circumvent G1 arrest imposed by overexpression of p16{sup INK4a}, but with less efficiency than the high-risk HPV16 E7. Together, our data show that in vitro properties of these E7 proteins correlate with the epidemiological classification of HPV26, 53 and 66 as HPV types with an intermediate risk for cervical cancer development.

  16. The HBx oncoprotein of hepatitis B virus engages nucleophosmin to promote rDNA transcription and cellular proliferation.

    PubMed

    Ahuja, Richa; Kapoor, Neetu Rohit; Kumar, Vijay

    2015-08-01

    The pleiotropic HBx oncoprotein of hepatitis B virus is well known to promote the expression of ribosomal RNAs and several host proteins that are known to support the development and progression of hepatocellular carcinoma (HCC). While overexpression of the nucleolar phosphoprotein, nucleophosmin (NPM), correlates with HCC progression, its upregulation by viral HBx and the resulting impact on perturbed nucleolar functions remain enigmatic. The present study shows that HBx up-regulates NPM levels and hijacks its functions to promote cellular proliferation. We found that HBx expression stabilizes NPM through post-translational modifications. Enhanced CDK2-mediated phosphorylation of NPM at Thr(199) upon HBx expression prevented its proteolytic cleavage and provided resistance to apoptosis. Further, HBx directly interacted with the C-terminal domain of NPM and got translocated into the nucleolus where it facilitated the recruitment of RNA polymerase I transcriptional machinery onto the rDNA promoter. Our results indicate that HBx enhances rDNA transcription via a novel regulatory mechanism involving acetylation of NPM and the subsequent depletion of histones from the rDNA promoter. Enhanced production of ribosomal RNA resulting from co-expression of HBx and NPM promoted ribosome biogenesis, cellular proliferation and transformation. Taken together, our study strongly suggests an important role of NPM in mediating the oncogenic effects of HBx and the corresponding nucleolar perturbations induced by this viral oncoprotein. PMID:25918010

  17. HPV18 E1^E4 is assembled into aggresome-like compartment and involved in sequestration of viral oncoproteins.

    PubMed Central

    Kajitani, Naoko; Satsuka, Ayano; Yoshida, Satoshi; Sakai, Hiroyuki

    2013-01-01

    Papillomavirus is the etiological agent for warts and several squamous carcinomas. Skin cancer induced by cottontail rabbit papillomavirus was the first animal model for virus-induced carcinogenesis. The target organ of the virus infection is stratified epithelium and virus replication is tightly regulated by the differentiation program of the host cell. E1^E4 protein is a viral gene product, and although it is considered to be involved in the control of virus replication, little is known about the biological role. We found that HPV18 E1^E4 was assembled into an aggresome-like compartment and was involved in sequestration of virus oncoproteins, which might contribute to the differentiation-dependent lifecycle of papillomavirus. PMID:23986755

  18. Targeted degradation of the AML1/MDS1/EVI1 oncoprotein by arsenic trioxide.

    PubMed

    Shackelford, David; Kenific, Candia; Blusztajn, Agnieszka; Waxman, Samuel; Ren, Ruibao

    2006-12-01

    Arsenic trioxide (ATO) has been found to be an effective treatment for acute promyelocytic leukemia patients and is being tested for treating other hematologic malignancies. We have previously shown that AML1/MDS1/EVI1 (AME), a fusion gene generated by a t(3;21)(q26;q22) translocation found in patients with chronic myelogenous leukemia during blast phase, myelodysplastic syndrome, or acute myelogenous leukemia (AML), impairs hematopoiesis and eventually induces an AML in mice. Both fusion partners of AME, AML1 and MDS1/EVI1, encode transcription factors and are also targets of a variety of genetic abnormalities in human hematologic malignancies. In addition, aberrant expression of ectopic viral integration site 1 (EVI1) has also been found in solid tumors, such as ovarian and colon cancers. In this study, we examined whether ATO could target AME and related oncoproteins. We found that ATO used at therapeutic levels degrades AME. The ATO treatment induces differentiation and apoptosis in AME leukemic cells in vitro as well as reduces tumor load and increases the survival of mice transplanted with these cells. We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers. PMID:17145882

  19. ?B-Crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer

    PubMed Central

    Moyano, Jose V.; Evans, Joseph R.; Chen, Feng; Lu, Meiling; Werner, Michael E.; Yehiely, Fruma; Diaz, Leslie K.; Turbin, Dmitry; Karaca, Gamze; Wiley, Elizabeth; Nielsen, Torsten O.; Perou, Charles M.; Cryns, Vincent L.

    2006-01-01

    Recent gene profiling studies have identified a new breast cancer subtype, the basal-like group, which expresses genes characteristic of basal epithelial cells and is associated with poor clinical outcomes. However, the genes responsible for the aggressive behavior observed in this group are largely unknown. Here we report that the small heat shock protein ?-basic–crystallin (?B-crystallin) was commonly expressed in basal-like tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. We also demonstrate that overexpression of ?B-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, ?B-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing ?B-crystallin by RNA interference inhibited these abnormalities. ?B-Crystallin overexpression also induced EGF- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the MAPK kinase/ERK (MEK/ERK) pathway. Moreover, the transformed phenotype conferred by ?B-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing ?B-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that ?B-crystallin is a novel oncoprotein expressed in basal-like breast carcinomas that independently predicts shorter survival. Our data also implicate the MEK/ERK pathway as a potential therapeutic target for these tumors. PMID:16395408

  20. A transcription assay for EWS oncoproteins in Xenopus oocytes.

    PubMed

    Ng, King Pan; Cheung, Felix; Lee, Kevin A W

    2010-10-01

    Aberrant chromosomal fusion of the Ewing's sarcoma oncogene (EWS) to several different cellular partners produces the Ewing's family of oncoproteins (EWS-fusion-proteins, EFPs) and associated tumors (EFTs). EFPs are potent transcriptional activators, dependent on the N-terminal region of EWS (the EWS-activation-domain, EAD) and this function is thought to be central to EFT oncogenesis and maintenance. Thus EFPs are promising therapeutic targets, but detailed molecular studies will be pivotal for exploring this potential. Such studies have so far largely been restricted to intact mammalian cells while recent evidence has indicated that a mammalian cell-free transcription system may not support bona fide EAD function. Therefore, the lack of manipulatable assays for the EAD presents a significant barrier to progress. Using Xenopus laevis oocytes we describe a plasmid-based micro-injection assay that supports efficient, bona fide EAD transcriptional activity and hence provides a new vehicle for molecular dissection of the EAD. PMID:21204019

  1. Activation of human papillomavirus type 18 E6-E7 oncogene expression by transcription factor Sp1.

    PubMed Central

    Hoppe-Seyler, F; Butz, K

    1992-01-01

    The human papillomavirus 18 (HPV18) E6 and E7 proteins are considered to be primarily responsive for the transforming activity of the virus. In order to analyse the molecular mechanisms resulting in viral oncoprotein expression, it is necessary to identify the factors involved in the transcriptional regulation of the E6/E7 genes. Here we define by gel retardation experiments a sequence aberrant Sp1 binding site present in the promoter proximal part of the viral transcriptional control region (Upstream Regulatory Region, URR). Functional analyses employing transient reporter assays reveal that this Sp1 element is required for an efficient stimulation of the HPV18 E6/E7-promoter. Mutation of the Sp1 element in the natural context of the HPV18 URR leads to a strong decrease in the activity of the E6/E7-promoter in several cell lines. The magnitude of reduction varies between different cell types and is higher in cell lines of epithelial origin when compared with nonepithelial cells. Cotransfection assays using Sp1 expression vector systems further define the promoter proximal HPV18 Sp1 binding motif as a functional Sp1 element in vivo and show that its integrity is essential for the stimulation of the E6/E7-promoter by augmented levels of Sp1. These results indicate, that the cellular transcription factor Sp1 plays an important role for the stimulation of the E6/E7-promoter by the viral URR and represents a major determinant for the expression of HPV18 transforming genes E6 and E7. Images PMID:1336181

  2. Phage display for site-specific immunization and characterization of high-risk human papillomavirus specific E7 monoclonal antibodies.

    PubMed

    Lidqvist, Maria; Nilsson, Olle; Holmgren, Jan; Hall, Christina; Fermér, Christian

    2008-09-15

    The paper describes a method to use filamentous phage to display specific regions of proteins for immunization in order to direct the immune response towards a pre-defined region of the protein. The method called site-specific immunization (SSI) was evaluated using the E7 protein of oncogenic (high-risk) human papillomavirus (HPV) type 16 as a model system. This protein consists of sequence blocks also present in other viral and cellular proteins and in the corresponding protein of low-risk HPVs. A fragment of the HPV16 E7 oncoprotein specific for a group of high-risk viruses was identified by sequence comparison and displayed on filamentous phages in fusion with the major phage coat protein VIII. The recombinant phages triggered an immune response in mice against the full-length HPV16 E7 protein. Fusion of B-lymphocytes from the immunized animals with myeloma cells resulted in three hybridomas producing monoclonal antibodies (MAbs) with reactivity against the endogenous E7 protein. The specificity of the MAbs for the HPV16 E7 protein in cancer cell lines was confirmed by Western blot analyses and immunocytochemistry. The epitope of each MAb was roughly mapped by determining the reactivity against overlapping E7 fragments displayed on phage particles. The mimotopes of the MAbs were further determined by biopanning against a randomized peptide library displayed on phage and found to be unique for a sub-set of high-risk HPV E7 proteins. The combination of different phage display techniques for immunization and epitope mapping was efficient for generation and characterization of highly specific MAbs. PMID:18606164

  3. Ha-ras and ?-catenin oncoproteins orchestrate metabolic programs in mouse liver tumors.

    PubMed

    Unterberger, Elif B; Eichner, Johannes; Wrzodek, Clemens; Lempiäinen, Harri; Luisier, Raphaëlle; Terranova, Rémi; Metzger, Ute; Plummer, Simon; Knorpp, Thomas; Braeuning, Albert; Moggs, Jonathan; Templin, Markus F; Honndorf, Valerie; Piotto, Martial; Zell, Andreas; Schwarz, Michael

    2014-10-01

    The process of hepatocarcinogenesis in the diethylnitrosamine (DEN) initiation/phenobarbital (PB) promotion mouse model involves the selective clonal outgrowth of cells harboring oncogene mutations in Ctnnb1, while spontaneous or DEN-only-induced tumors are often Ha-ras- or B-raf-mutated. The molecular mechanisms and pathways underlying these different tumor sub-types are not well characterized. Their identification may help identify markers for xenobiotic promoted versus spontaneously occurring liver tumors. Here, we have characterized mouse liver tumors harboring either Ctnnb1 or Ha-ras mutations via integrated molecular profiling at the transcriptional, translational and post-translational levels. In addition, metabolites of the intermediary metabolism were quantified by high resolution (1)H magic angle nuclear magnetic resonance. We have identified tumor genotype-specific differences in mRNA and miRNA expression, protein levels, post-translational modifications, and metabolite levels that facilitate the molecular and biochemical stratification of tumor phenotypes. Bioinformatic integration of these data at the pathway level led to novel insights into tumor genotype-specific aberrant cell signaling and in particular to a better understanding of alterations in pathways of the cell intermediary metabolism, which are driven by the constitutive activation of the ?-Catenin and Ha-ras oncoproteins in tumors of the two genotypes. PMID:24535843

  4. Bovine papillomavirus type 1 DNA and E5 oncoprotein expression in water buffalo fibropapillomas.

    PubMed

    Silvestre, O; Borzacchiello, G; Nava, D; Iovane, G; Russo, V; Vecchio, D; D'Ausilio, F; Gault, E A; Campo, M S; Paciello, O

    2009-07-01

    Papillomas and fibropapillomas may occur in the skin and in different organs in animals. Ten different genotypes of bovine papillomavirus (BPV) have been identified. BPV-1 through BPV-10 are all strictly species-specific, but BPV-1/2 may also infect other species such as equids, inducing fibroblastic tumors. BPV-1 and BPV-2 are associated with fibropapillomas in cattle; these tumors are formed by excessive proliferation of virus-infected dermal fibroblasts and epidermal keratinocytes. Nine water buffalo (Bubalus bubalis) were examined for the presence of multiple cutaneous and perivulvar tumors. Cutaneous and perivulvar fibropapillomatosis were confirmed histologically. Negative-stain transmission electron microscopic examination revealed papillomavirus-like particles in the fibropapillomas, and papillomaviral DNA was also detected by the polymerase chain reaction. The amplified long control region (LCR) DNA sequence was identical to that of BPV-1. The BPV-1 E5 oncoprotein was strongly expressed in the tumor cells thus confirming a causal role of the virus. This article represents the first report of cutaneous, perivulvar, and vulvar fibropapilloma associated with BPV-1 infection in the water buffalo and describes another example of cross-species infection by BPV-1. PMID:19276046

  5. Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein

    PubMed Central

    Suzuki, Nobumi; Murata-Kamiya, Naoko; Yanagiya, Kohei; Suda, Wataru; Hattori, Masahira; Kanda, Hiroaki; Bingo, Atsuhiro; Fujii, Yumiko; Maeda, Shin; Koike, Kazuhiko; Hatakeyama, Masanori

    2015-01-01

    Helicobacter pylori cagA-positive strain delivers the CagA oncoprotein into gastric epithelial cells and at the same time elicits stomach inflammation. To experimentally investigate the pathophysiological interplay between CagA and inflammation, transgenic mice systemically expressing the bacterial cagA gene were treated with a colitis inducer, dextran sulfate sodium (DSS). Compared with control mice, DSS-induced colitis was markedly deteriorated in cagA-transgenic mice. In the colonic epithelia of cagA-transgenic mice, there was a substantial decrease in the level of I?B, which binds and sequesters NF-?B in the cytoplasm. This I?B reduction was due to CagA-mediated inhibition of PAR1, which may stimulate I?B degradation by perturbing microtubule stability. Whereas the CagA-mediated I?B reduction did not automatically activate NF-?B, it lowered the threshold of NF-?B activation by inflammogenic insults, thereby contributing to colitis exacerbation in cagA-transgenic mice. CagA also activates inflammasomes independently of NF-?B signaling, which further potentiates inflammation. The incidence of colonic dysplasia was elevated in DSS-treated cagA-transgenic mice due to a robust increase in the number of pre-cancerous flat-type dysplasias. Thus, CagA deteriorated inflammation, whereas inflammation strengthened the oncogenic potential of CagA. This work revealed that H. pylori CagA and inflammation reinforce each other in creating a downward spiral that instigates neoplastic transformation. PMID:25944120

  6. Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

    PubMed Central

    Jin, Caining; Kufe, Donald

    2014-01-01

    The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQC?AQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-?B, occupies the IL-8 promoter with NF-?B, and induces IL-8 transcription. MUC1-C also induces NF-?B-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-?B?IL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population. PMID:24770886

  7. Quercetin elevates p27(Kip1) and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1.

    PubMed

    Beniston, Richard Garry; Campo, Maria Saveria

    2003-08-21

    Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27(Kip1). Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27(Kip1) with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27(Kip1) was due not only to increased protein half-life, but also to increased mRNA transcription. PMID:12934110

  8. Enhanced Immunogenicity of HPV 16 E7 Fusion Proteins in DNA Vaccination

    Microsoft Academic Search

    Nico Michel; Wolfram Osen; Lutz Gissmann; Ton N. M Schumacher; Hanswalter Zentgraf; Martin Müller

    2002-01-01

    DNA vaccination is a promising approach for inducing both humoral and cellular immune responses. For immunotherapy of HPV-16-associated diseases the E7 protein is considered a prime candidate, as it is expressed in all HPV-16-positive tumors. Unfortunately, the E7 protein is a very poor inducer of a cytotoxic T-cell response, when being used as antigen in DNA vaccination. Here we demonstrate

  9. E7 groups from octonionic magic square

    E-print Network

    Sergio L. Cacciatori; Francesco Dalla Piazza; Antonio Scotti

    2011-11-08

    In this paper we continue our program, started in [2], of building up explicit generalized Euler angle parameterizations for all exceptional compact Lie groups. Here we solve the problem for E7, by first providing explicit matrix realizations of the Tits construction of a Magic Square product between the exceptional octonionic algebra J and the quaternionic algebra H, both in the adjoint and the 56 dimensional representations. Then, we provide the Euler parametrization of E7 starting from its maximal subgroup U=(E6 x U(1))/Z3. Next, we give the constructions for all the other maximal compact subgroups.

  10. E7 groups from octonionic magic square

    E-print Network

    Cacciatori, Sergio L; Scotti, Antonio

    2010-01-01

    In this paper we continue our program, started in [1], of building up explicit generalized Euler angle parameterizations for all exceptional compact Lie groups. Here we solve the problem for E7, by first providing explicit matrix realizations of the Tits construction of a Magic Square product between the exceptional octonionic algebra J and the quaternionic algebra H, both in the adjoint and the 56 dimensional representations. Then, we provide the Euler parametrization of E7 starting from its maximal subgroup U=(E6 x U(1))/Z_3.

  11. NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells

    E-print Network

    Miyamoto, Shigeki

    NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells Pei-Yun Chang, 1 Kyle Abstract We recently showed that a subset of human T acute lymphoblastic leukemia (T-ALL) cell lines in CEM T leukemia cells, basal NFKB1 expression is increased, and the levels of p65:cRel complex

  12. GENETIC ANALYSYS OF THE IN VIVO FUNCTION AND REGULATION OF THE ONCOPROTEIN CDK8 IN DROSOPHILA 

    E-print Network

    Park, Gee Yoon

    2012-05-09

    Cyclin-Dependent Kinase 8 (CDK8) has recently emerged as an oncoprotein that is amplified in both colorectal and melanoma cancers. The importance of CDK8 and its regulatory partner Cyclin C (CycC) is highlighted by the clinical observations showing...

  13. ERG oncoprotein expression in prostate carcinoma patients of different ethnicities.

    PubMed

    Kelly, Gregory M; Kong, Yink Heay; Dobi, Albert; Srivastava, Shiv; Sesterhenn, Isabell A; Pathmanathan, Rajadurai; Tan, Hui Meng; Tan, Shyh-Han; Cheong, Sok Ching

    2015-01-01

    Overexpression of the erythroblast transformation-specific-related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)-ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin-fixed paraffin-embedded sections of transrectal ultrasound-guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti-ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (P=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (P=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG-expressing tumors among MI patients suggested that the TMPRSS2-ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology of CaP initiation and progression between ethnic groups. PMID:25469265

  14. Combination of hTERT and bmi-1, E6, or E7 Induces Prolongation of the Life Span of Bone Marrow Stromal Cells from an Elderly Donor without Affecting Their Neurogenic Potential†

    PubMed Central

    Mori, Taisuke; Kiyono, Tohru; Imabayashi, Hideaki; Takeda, Yukiji; Tsuchiya, Kohei; Miyoshi, Shunichirou; Makino, Hatsune; Matsumoto, Kenji; Saito, Hirohisa; Ogawa, Satoshi; Sakamoto, Michiie; Hata, Jun-Ichi; Umezawa, Akihiro

    2005-01-01

    Murine bone marrow stromal cells differentiate not only into mesodermal derivatives, such as osteocytes, chondrocytes, adipocytes, skeletal myocytes, and cardiomyocytes, but also into neuroectodermal cells in vitro. Human bone marrow stromal cells are easy to isolate but difficult to study because of their limited life span. To overcome this problem, we attempted to prolong the life span of bone marrow stromal cells and investigated whether bone marrow stromal cells modified with bmi-1, hTERT, E6, and E7 retained their differentiated capability, or multipotency. In this study, we demonstrated that the life span of bone marrow stromal cells derived from a 91-year-old donor could be extended and that the stromal cells with an extended life span differentiated into neuronal cells in vitro. We examined the neuronally differentiated cells morphologically, physiologically, and biologically and compared the gene profiles of undifferentiated and differentiated cells. The neuronally differentiated cells exhibited characteristics similar to those of midbrain neuronal progenitors. Thus, the results of this study support the possible use of autologous-cell graft systems to treat central nervous system diseases in geriatric patients. PMID:15923633

  15. The high-risk HPV E6 oncoprotein preferentially targets phosphorylated nuclear forms of hDlg

    SciTech Connect

    Narayan, Nisha; Subbaiah, Vanitha Krishna [Tumour Virology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste, TS 34012 (Italy); Banks, Lawrence, E-mail: banks@icgeb.or [Tumour Virology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste, TS 34012 (Italy)

    2009-04-25

    High-risk mucosal HPV E6 oncoproteins target a number of PDZ domain-containing substrates for proteasome mediated degradation. One of these, Discs Large (Dlg), is involved in the regulation of cell polarity and proliferation control. Previous studies had suggested that Dlg when hyperphosphorylated by osmotic shock, or when present in the nucleus could be preferentially targeted by E6. In this study we use phospho-specific antibodies directed against Dlg phosphorylated at residues S158 and S442 to show that these two observations are, in fact, linked. Dlg, when phosphorylated on S158 and S442 by CDK1 or CDK2, shows a preferential nuclear accumulation. However, these forms of Dlg are absent in cells derived from HPV-induced cervical cancers. Upon either proteasome inhibition or siRNA ablation of E6 expression, we see specific rescue of these phosphorylated forms of Dlg. These results demonstrate that nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites has enhanced susceptibility to E6-induced degradation and place previous studies on the stress-induced phosphorylation of Dlg into a relevant biological context.

  16. Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation

    SciTech Connect

    Kong, Chen; Lange, Jeffrey J.; Samovski, Dmitri [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)] [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Su, Xiong [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States)] [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States); Liu, Jialiu [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)] [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Sundaresan, Sinju [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States)] [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States); Stahl, Philip D., E-mail: pstahl@wustl.edu [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2013-05-03

    Highlights: •Hominoid-specific oncogene TBC1D3 is targeted to plasma membrane by palmitoylation. •TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. •TBC1D3 palmitoylation governs growth factors-induced TBC1D3 degradation. •Post-translational modifications may regulate oncogenic properties of TBC1D3. -- Abstract: Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.

  17. Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

    PubMed

    Ramirez, Juan; Poirson, Juline; Foltz, Clémence; Chebaro, Yassmine; Schrapp, Maxime; Meyer, Amandine; Bonetta, Anaëlle; Forster, Anne; Jacob, Yves; Masson, Murielle; Deryckère, François; Travé, Gilles

    2015-06-26

    The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6?proteins tested but not to low-risk mucosal or cutaneous HPV?E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase?3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers. PMID:26014966

  18. Predicted alpha-helix/beta-sheet secondary structures for the zinc-binding motifs of human papillomavirus E7 and E6 proteins by consensus prediction averaging and spectroscopic studies of E7.

    PubMed Central

    Ullman, C G; Haris, P I; Galloway, D A; Emery, V C; Perkins, S J

    1996-01-01

    The E7 and E6 proteins are the main oncoproteins of human papillomavirus types 16 and 18 (HPV-16 and HPV-18), and possess unknown protein structures. E7 interacts with the cellular tumour-suppressor protein pRB and contains a zinc-binding site with two Cys-Xaa2-Cys motifs spaced 29 or 30 residues apart. E6 interacts with another cellular tumour-suppressor protein p53 and contains two zinc-binding sites, each with two Cys-Xaa2-Cys motifs at a similar spacing of 29 or 30 residues. By using the GOR I/III, Chou-Fasman, SAPIENS and PHD methods, the effectiveness of consensus secondary structure predictions on zinc-finger proteins was first tested with sequences for 160 transcription factors and 72 nuclear hormone receptors. These contain Cys2His2 and Cys2Cys2 zinc-binding regions respectively, and possess known atomic structures. Despite the zinc- and DNA-binding properties of these protein folds, the major alpha-helix structures in both zinc-binding regions were correctly identified. Thus validated, the use of these prediction methods with 47 E7 sequences indicated four well-defined alpha-helix (alpha) and beta-sheet (beta) secondary structure elements in the order beta beta alpha beta in the zinc-binding region of E7 at its C-terminus. The prediction was tested by Fourier transform infrared spectroscopy of recombinant HPV-16 E7 in H2O and 2H2O buffers. Quantitative integration showed that E7 contained similar amounts of alpha-helix and beta-sheet structures, in good agreement with the averaged prediction of alpha-helix and beta-sheet structures in E7 and also with previous circular dichroism studies. Protein fold recognition analyses predicted that the structure of the zinc-binding region in E7 was similar to a beta beta alpha beta motif found in the structure of Protein G. This is consistent with the E7 structure predictions, despite the low sequence similarities with E7. This predicted motif is able to position four Cys residues in proximity to a zinc atom. A model for the zinc-binding motif of E7 was constructed by combining the Protein G coordinates with those for the zinc-binding site in transcription factor TFIIS. Similar analyses for the two zinc-binding motifs in E6 showed that they have different alpha/beta secondary structures from that in E7. When compared with 12 other zinc-binding proteins, these results show that E7 and E6 are predicted to possess novel types of zinc-binding structure. PMID:8870673

  19. Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation

    PubMed Central

    Kong, Chen; Lange, Jeffrey J.; Samovski, Dmitri; Su, Xiong; Liu, Jialiu; Sundaresan, Sinju; Stahl, Philip D.

    2013-01-01

    Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in-vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis. PMID:23578663

  20. Fowlpox virus recombinants expressing HPV-16 E6 and E7 oncogenes for the therapy of cervical carcinoma elicit humoral and cell-mediated responses in rabbits

    PubMed Central

    2010-01-01

    Background Around half million new cases of cervical cancer arise each year, making the development of an effective therapeutic vaccine against HPV a high priority. As the E6 and E7 oncoproteins are expressed in all HPV-16 tumour cells, vaccines expressing these proteins might clear an already established tumour and support the treatment of HPV-related precancerous lesions. Methods Three different immunisation regimens were tested in a pre-clinical trial in rabbits to evaluate the humoral and cell-mediated responses of a putative HPV-16 vaccine. Fowlpoxvirus (FP) recombinants separately expressing the HPV-16 E6 (FPE6) and E7 (FPE7) transgenes were used for priming, followed by E7 protein boosting. Results All of the protocols were effective in eliciting a high antibody response. This was also confirmed by interleukin-4 production, which increased after simultaneous priming with both FPE6 and FPE7 and after E7 protein boost. A cell-mediated immune response was also detected in most of the animals. Conclusion These results establish a preliminary profile for the therapy with the combined use of avipox recombinants, which may represent safer immunogens than vaccinia-based vectors in immuno-compromised individuals, as they express the transgenes in most mammalian cells in the absence of a productive replication. PMID:20409340

  1. The Human Papillomavirus Type 16 E7 Oncoprotein Activates the Fanconi Anemia (FA) Pathway and Causes Accelerated Chromosomal Instability in FA Cells

    Microsoft Academic Search

    Nicole Spardy; Anette Duensing; Domonique Charles; Nathan Haines; Tomomi Nakahara; Paul F. Lambert; Stefan Duensing

    2007-01-01

    Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the

  2. Fusion of CTLA-4 with HPV16 E7 and E6 Enhanced the Potency of Therapeutic HPV DNA Vaccine

    PubMed Central

    Gan, Lili; Jia, Rong; Zhou, Lili; Guo, Jihua; Fan, Mingwen

    2014-01-01

    Preventive anti-HPV vaccines are effective against HPV infection but not against existing HPV-associated diseases, including cervical cancer and other malignant diseases. Therefore, the development of therapeutic vaccines is urgently needed. To improve anti-tumor effects of therapeutic vaccine, we fused cytotoxic T-lymphocyte antigen 4 (CTLA-4) with HPV16 E7 and E6 as a fusion therapeutic DNA vaccine (pCTLA4-E7E6). pCTLA4-E7E6 induced significantly higher anti-E7E6 specific antibodies and relatively stronger specific CTL responses than the nonfusion DNA vaccine pE7E6 in C57BL/6 mice bearing with TC-1 tumors. pCTLA4-E7E6 showed relatively stronger anti-tumor effects than pE7E6 in therapeutic immunization. These results suggest that fusing CTLA-4 with E7E6 is a useful strategy to develop therapeutic HPV DNA vaccines. In addition, fusing the C-terminal of E7 with the N-terminal of E6 impaired the functions of both E7 and E6. PMID:25265018

  3. Novel perspective: exercise training stimulus triggers the expression of the oncoprotein human double minute-2 in human skeletal muscle

    PubMed Central

    Roudier, Emilie; Aiken, Julian; Slopack, Dara; Gouzi, Fares; Mercier, Jacques; Haas, Tara L; Gustafsson, Thomas; Hayot, Maurice; Birot, Olivier

    2013-01-01

    High expression levels of human double minute-2 (Hdm2) are often associated with increased risk of cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions of Hdm2 in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates expression of murine double minute-2 (Mdm2), the murine analog of Hdm2, in rodent skeletal muscle and Mdm2 was required for exercise-induced muscle angiogenesis. Here we showed that exercise training stimulated the expression of Hdm2 protein in human skeletal muscle from +38% to +81%. This robust physiological response was observed in 60–70% of the subjects tested, in both young and senior populations. Similarly, exercise training stimulated the expression of platelet endothelial cell adhesion molecule-1, an indicator of the level of muscle capillarization. Interestingly, a concomitant decrease in the tumor suppressor forkhead box O-1 (FoxO1) transcription factor levels did not occur with training although Mdm2/Hdm2 is known to inhibit FoxO1 expression in diseased skeletal muscle. This could suggest that Hdm2 has different targets when stimulated in a physiological context and that exercise training could be considered therapeutically in the context of cancer in combination with anti-Hdm2 drug therapies in order to preserve Hdm2 physiological functions in healthy tissues. PMID:24303114

  4. Merkel Cell Polyomavirus Small T Antigen Controls Viral Replication and Oncoprotein Expression by Targeting the Cellular Ubiquitin Ligase SCFFbw7

    PubMed Central

    Kwun, Hyun Jin; Shuda, Masahiro; Feng, Huichen; Camacho, Carlos J.; Moore, Patrick S.; Chang, Yuan

    2013-01-01

    SUMMARY Merkel cell polyomavirus (MCV) causes an aggressive human skin cancer, Merkel cell carcinoma, through expression of small T (sT) and large T (LT) viral oncoproteins. MCV sT is also required for efficient MCV DNA replication by the multifunctional MCV LT helicase protein. We find that LT is targeted for proteasomal degradation by the cellular SCFFbw7 E3 ligase, which can be inhibited by sT through its LT stabilization domain (LSD). Consequently, sT also stabilizes cellular SCFFbw7 targets, including the cell cycle regulators c-Myc and cyclin E. Mutating the sT LSD decreases LT protein levels and eliminates synergism in MCV DNA replication as well as sT-induced cell transformation. SCFFbw7 knockdown mimics sT-mediated stabilization of LT, but this knockdown is insufficient to fully reconstitute the transforming activity of a mutant LSD sT protein. Thus, MCV has evolved a regulatory system involving SCFFbw7 that controls viral replication but also contributes to host cell transformation. PMID:23954152

  5. Novel perspective: exercise training stimulus triggers the expression of the oncoprotein human double minute-2 in human skeletal muscle.

    PubMed

    Roudier, Emilie; Aiken, Julian; Slopack, Dara; Gouzi, Fares; Mercier, Jacques; Haas, Tara L; Gustafsson, Thomas; Hayot, Maurice; Birot, Olivier

    2013-07-01

    High expression levels of human double minute-2 (Hdm2) are often associated with increased risk of cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions of Hdm2 in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates expression of murine double minute-2 (Mdm2), the murine analog of Hdm2, in rodent skeletal muscle and Mdm2 was required for exercise-induced muscle angiogenesis. Here we showed that exercise training stimulated the expression of Hdm2 protein in human skeletal muscle from +38% to +81%. This robust physiological response was observed in 60-70% of the subjects tested, in both young and senior populations. Similarly, exercise training stimulated the expression of platelet endothelial cell adhesion molecule-1, an indicator of the level of muscle capillarization. Interestingly, a concomitant decrease in the tumor suppressor forkhead box O-1 (FoxO1) transcription factor levels did not occur with training although Mdm2/Hdm2 is known to inhibit FoxO1 expression in diseased skeletal muscle. This could suggest that Hdm2 has different targets when stimulated in a physiological context and that exercise training could be considered therapeutically in the context of cancer in combination with anti-Hdm2 drug therapies in order to preserve Hdm2 physiological functions in healthy tissues. PMID:24303114

  6. HPV16-E7 Expression in Squamous Epithelium Creates a Local Immune Suppressive Environment via CCL2- and CCL5- Mediated Recruitment of Mast Cells

    PubMed Central

    Bergot, Anne-Sophie; Ford, Neill; Leggatt, Graham R.

    2014-01-01

    Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions. PMID:25340820

  7. Intracellular Analysis of the Interaction between the Human Papillomavirus Type 16 E6 Oncoprotein and Inhibitory Peptides

    PubMed Central

    Stutz, Christina; Reinz, Eileen; Honegger, Anja; Bulkescher, Julia; Schweizer, Johannes; Zanier, Katia; Travé, Gilles; Lohrey, Claudia; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

    2015-01-01

    Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention. PMID:26151636

  8. Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC.

    PubMed

    Romeo, Megan M; Ko, Bookyung; Kim, Janice; Brady, Rebecca; Heatley, Hayley C; He, Jeffrey; Harrod, Carolyn K; Barnett, Braden; Ratner, Lee; Lairmore, Michael D; Martinez, Ernest; Lüscher, Bernhard; Robson, Craig N; Henriksson, Marie; Harrod, Robert

    2015-02-01

    The human T-cell leukemia retrovirus type-1 (HTLV-1) p30(II) protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30(II) interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30(II) and c-MYC remain to be completely understood. Herein we demonstrate that p30(II) induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys?Arg substitution mutants are impaired for oncogenic transformation with p30(II) in c-myc(-/-) HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30(II) is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30(II) inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30(II)/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. PMID:25569455

  9. GLIPR1 Suppresses Prostate Cancer Development through Targeted Oncoprotein Destruction

    PubMed Central

    Li, Likun; Ren, Chengzhen; Yang, Guang; Fattah, Elmoataz Abdel; Goltsov, Alexei A.; Kim, Soo Mi; Lee, Ju-Seog; Park, Sanghee; Demayo, Francesco J.; Ittmann, Michael M.; Troncoso, Patricia; Thompson, Timothy C.

    2013-01-01

    Downregulation of the proapoptotic p53 target gene GLIPR1 occurs frequently in prostate cancer (PCa), but the functional meaning of this event is obscure. Here we report the discovery of functional relationship between GLIPR1 and c-Myc in PCa where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human PCa. Restoration of GLIPR1 expression in PCa cells downregulated c-myc levels, inhibiting cell cycle progression. Downregulation was linked to a reduction in ?-catenin/TCF4-mediated transcription of the c-myc gene, which were caused by GLIPR1-mediated redistribution of casein kinase 1? (CK1?) from the Golgi apparatus to the cytoplasm where CK1? could phosphorylate ?-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3?- and/or CK1?-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia (PIN) and PCa. Together, our findings provide evidence for CK1?-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1? phosphorylation site for c-Myc degradation. Further, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. PMID:22025562

  10. The E6 and E7 Proteins of the Cutaneous Human Papillomavirus Type 38 Display Transforming Properties

    Microsoft Academic Search

    Sandra Caldeira; Ingeborg Zehbe; Rosita Accardi; Ilaria Malanchi; Wen Dong; Marianna Giarre; Ethel-Michele de Villiers; Raffaele Filotico; Petra Boukamp; Massimo Tommasino

    2003-01-01

    Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces

  11. GLIPR1 suppresses prostate cancer development through targeted oncoprotein destruction.

    PubMed

    Li, Likun; Ren, Chengzhen; Yang, Guang; Fattah, Elmoataz Abdel; Goltsov, Alexei A; Kim, Soo Mi; Lee, Ju-Seog; Park, Sanghee; Demayo, Francesco J; Ittmann, Michael M; Troncoso, Patricia; Thompson, Timothy C

    2011-12-15

    Downregulation of the proapoptotic p53 target gene glioma pathogenesis-related protein 1 (GLIPR1) occurs frequently in prostate cancer, but the functional meaning of this event is obscure. Here, we report the discovery of functional relationship between GLIPR1 and c-Myc in prostate cancer where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human prostate cancer. Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. Downregulation was linked to a reduction in ?-catenin/TCF4-mediated transcription of the c-myc gene, which was caused by GLIPR1-mediated redistribution of casein kinase 1? (CK1?) from the Golgi apparatus to the cytoplasm where CK1? could phosphorylate ?-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3?- and/or CK1?-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia and prostate cancer. Together, our findings provide evidence for CK1?-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1? phosphorylation site for c-Myc degradation. Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. PMID:22025562

  12. COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP.

    PubMed

    Sharma-Walia, N; Patel, K; Chandran, K; Marginean, A; Bottero, V; Kerur, N; Paul, A G

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-?B, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-?B-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-?B induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating 'extrinsic' as well as 'intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial-mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13. PMID:23552603

  13. COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP

    PubMed Central

    Sharma-Walia, N; Patel, K; Chandran, K; Marginean, A; Bottero, V; Kerur, N; Paul, A G

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-?B, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-?B-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-?B induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial–mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13. PMID:23552603

  14. High incidence of female reproductive tract cancers in FA deficient HPV16 transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins

    PubMed Central

    Park, Jung Wook; Shin, Myeong-Kyun; Lambert, Paul F.

    2014-01-01

    Fanconi anemia (FA) is a rare genetic disorder caused by defects in a DNA damage repair system, the FA pathway. FA patients frequently develop squamous cell carcinoma (SCC) at sites that are associated with HPV-driven cancer including the female reproductive tract. To assess experimentally whether FA deficiency increases susceptibility to HPV-associated cervical/vaginal cancer, we monitored cancer incidence in the female lower reproductive tract of FA-deficient mice expressing HPV16 oncogenes, E6 and/or E7. FA deficiency specifically increased the incidence of cancers in mice expressing E7; but, this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of ?-H2AX and 53BP1 nuclear-foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of ‘pocket’ proteins, pRb, p107, and p130, which are established targets of E7. Our findings support the hypothesis that E7 induces cancer by causing DNA damage at least in part through the inactivation of pocket proteins. This hypothesis explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. PMID:24013229

  15. High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins.

    PubMed

    Park, J W; Shin, M-K; Lambert, P F

    2014-06-26

    Fanconi anemia (FA) is a rare genetic disorder caused by defects in a DNA damage repair system, the FA pathway. FA patients frequently develop squamous cell carcinoma (SCC) at sites that are associated with human papillomavirus (HPV)-driven cancer including the female reproductive tract. To assess experimentally whether FA deficiency increases susceptibility to HPV-associated cervical/vaginal cancer, we monitored cancer incidence in the female lower reproductive tract of FA-deficient mice expressing HPV16 oncogenes, E6 and/or E7. FA deficiency specifically increased the incidence of cancers in mice expressing E7; but this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of ?-H2AX and 53BP1 (p53 binding protein 1) nuclear foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of 'pocket' proteins, pRb, p107 and p130, which are established targets of E7. Our findings support the hypothesis that E7 induces cancer by causing DNA damage at least in part through the inactivation of pocket proteins. This hypothesis explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. PMID:24013229

  16. Therapeutic DNA vaccination against colorectal cancer by targeting the MYB oncoprotein

    PubMed Central

    Cross, Ryan S; Malaterre, Jordane; Davenport, Alexander J; Carpinteri, Sandra; Anderson, Robin L; Darcy, Phillip K; Ramsay, Robert G

    2015-01-01

    Cancers can be addicted to continued and relatively high expression of nuclear oncoproteins. This is evident in colorectal cancer (CRC) where the oncoprotein and transcription factor MYB is over expressed and essential to continued proliferation and tumour cell survival. Historically, targeting transcription factors in the context of cancer has been very challenging. Nevertheless, we formulated a DNA vaccine to generate a MYB-specific immune response in the belief MYB peptides might be aberrantly presented on the cell surface of CRC cells. MYB, like many tumour antigens, is weakly immunogenic as it is a ‘self' antigen and is subject to tolerance. To break tolerance, a fusion vaccine was generated comprising a full-length MYB complementary DNA (cDNA) flanked by two potent CD4-epitopes derived from tetanus toxoid. Vaccination was achieved against tumours initiated by two distinct highly aggressive, syngeneic cancer cell lines (CT26 and MC38) that express MYB. This was done in BALB/c and C57BL/6 mouse strains respectively. We introduced multiple inactivating mutations into the oncogene sequence for safety and sub-cloned the cDNA into a Food and Drug Administration (FDA)-compliant vector. We used low dose cyclophosphamide (CY) to overcome T-regulatory cell immune suppression, and anti-program cell death receptor 1 (anti-PD-1) antibodies to block T-cell exhaustion. Anti-PD-1 administered alone slightly delayed tumour growth in MC38 and more effectively in CT26 bearing mice, while CY treatment alone did not. We found that therapeutic vaccination elicits protection when MC38 tumour burden is low, mounts tumour-specific cell killing and affords enhanced protection when MC38 and CT26 tumour burden is higher but only in combination with anti-PD-1 antibody or low dose CY, respectively. PMID:25671128

  17. Oct4 Is Required ?E7.5 for Proliferation in the Primitive Streak

    PubMed Central

    DeVeale, Brian; Brokhman, Irina; Mohseni, Paria; Babak, Tomas; Yoon, Charles; Lin, Anthony; Onishi, Kento; Tomilin, Alexey; Pevny, Larysa; Zandstra, Peter W.; Nagy, Andras; van der Kooy, Derek

    2013-01-01

    Oct4 is a widely recognized pluripotency factor as it maintains Embryonic Stem (ES) cells in a pluripotent state, and, in vivo, prevents the inner cell mass (ICM) in murine embryos from differentiating into trophectoderm. However, its function in somatic tissue after this developmental stage is not well characterized. Using a tamoxifen-inducible Cre recombinase and floxed alleles of Oct4, we investigated the effect of depleting Oct4 in mouse embryos between the pre-streak and headfold stages, ?E6.0–E8.0, when Oct4 is found in dynamic patterns throughout the embryonic compartment of the mouse egg cylinder. We found that depletion of Oct4 ?E7.5 resulted in a severe phenotype, comprised of craniorachischisis, random heart tube orientation, failed turning, defective somitogenesis and posterior truncation. Unlike in ES cells, depletion of the pluripotency factors Sox2 and Oct4 after E7.0 does not phenocopy, suggesting that ?E7.5 Oct4 is required within a network that is altered relative to the pluripotency network. Oct4 is not required in extraembryonic tissue for these processes, but is required to maintain cell viability in the embryo and normal proliferation within the primitive streak. Impaired expansion of the primitive streak occurs coincident with Oct4 depletion ?E7.5 and precedes deficient convergent extension which contributes to several aspects of the phenotype. PMID:24244203

  18. An improved rearranged Human Papillomavirus Type 16 E7 DNA vaccine candidate (HPV16 E7SH) induces an E7 wildtype-specific T cell response

    Microsoft Academic Search

    Peter Öhlschläger; Michaela Pes; Wolfram Osen; Matthias Dürst; Achim Schneider; Lutz Gissmann; Andreas M. Kaufmann

    2006-01-01

    A new and very promising approach in vaccine development is the application of naked DNA. In comparison to conventional vaccines it offers several advantages, especially if there is a need for the development of low cost vaccines. Infection with high-risk human papillomaviruses (hr-HPVs) is the major risk factor for the development of cervical cancer (cc), the third most common cancer

  19. Bcl2 Oncoprotein Blocks Chemotherapy-Induced Apoptosis in a Human Leukemia Cell Line

    Microsoft Academic Search

    Toshiyuki Miyashita; John C. Reed

    1993-01-01

    HE bcl-2 gene was initially discovered by virtue of its T involvement in t( 14; 181 (q32;q21) chromosomal translocations that are found in the majority of non-Hodg- kin's lymphomas (NHLs).' This gene encodes a 26-Kd in- tegral membrane protein that appears to reside at least in part in mitochondria, and that promotes the survival of sev- eral types of hematolymphoid

  20. Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice.

    PubMed

    Ballon, Gianna; Chen, Kang; Perez, Rocio; Tam, Wayne; Cesarman, Ethel

    2011-03-01

    Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-?, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell-derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell-associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents. PMID:21339646

  1. Human Papillomavirus Type 5 E6 Oncoprotein Represses the Transforming Growth Factor   Signaling Pathway by Binding to SMAD3

    Microsoft Academic Search

    Jose-Andres Mendoza; Yves Jacob; Patricia Cassonnet; Michel Favre

    2006-01-01

    Mechanisms of cellular transformation associated with human papillomavirus type 5 (HPV5), which is responsible for skin carcinomas in epidermodysplasia verruciformis (EV) patients, are poorly understood. Using a yeast two-hybrid screening and molecular and cellular biology experiments, we found that HPV5 oncoprotein E6 interacts with SMAD3, a key component in the transforming growth factor 1 (TGF-1) signaling pathway. HPV5 E6 inhibits

  2. Lack of correlation between expression of Epstein-Barr virus (EBV) latent membrane protein and bcl-2 oncoprotein in vivo

    Microsoft Academic Search

    Q Tao; G Srivastava; S L Loke; F C Ho

    1994-01-01

    AIMS--To evaluate whether there is any correlation between the expression of Epstein-Barr virus (EBV) latent membrane protein (LMP) and oncoprotein bcl-2 in the lymph node biopsy specimens of a Chinese patient with EBV-related reactive lymphoproliferation who later developed T cell lymphoma after a short period of time. METHODS--Immunohistochemistry, with a standard alkaline phosphatase antialkaline phosphatase (APAAP) method and New Fuchsin

  3. The T Cell Leukemia Oncoprotein SCL\\/tal-1 Is Essential for Development of All Hematopoietic Lineages

    Microsoft Academic Search

    Catherine Porcher; Wojciech Swat; Karen Rockwell; Yuko Fujiwara; Frederick W Alt; Stuart H Orkin

    1996-01-01

    The T cell leukemia oncoprotein SCL\\/tal-1, a basic–helix-loop-helix transcription factor, is required for production of embryonic red blood cells in the mouse yolk sac. To define roles in other lineages, we studied the hematopoietic potential of homozygous mutant SCL\\/tal-1 ?\\/? embryonic stem cells upon in vitro differentiation and in vivo in chimeric mice. Here we show that in the absence

  4. Inactivation of Ret\\/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI1

    Microsoft Academic Search

    C. Lanzi; G. Cassinelli; G. Cuccuru; N. Zaffaroni; R. Supino; S. Vignati; C. Zanchi; M. Yamamoto; F. Zunino

    2003-01-01

    Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpd1) on the tyrosine kinase activity and transforming ability of the products of the RET\\/PTC1 oncogene

  5. Nuclear Entry of High-Risk Human Papillomavirus Type 16 E6 Oncoprotein Occurs via Several Pathways

    PubMed Central

    Le Roux, Lucia G.; Moroianu, Junona

    2003-01-01

    The E6 oncoprotein of high-risk human papillomavirus type 16 (HPV16) interacts with several nuclear transcription factors and coactivators in addition to cytoplasmic proteins, suggesting that nuclear import of HPV16 E6 plays a role in the cellular transformation process. In this study we have investigated the nuclear import pathways of HPV16 E6 in digitonin-permeabilized HeLa cells. We found that HPV16 E6 interacted with the karyopherin (Kap) ?2 adapter and could enter the nucleus via a classical Kap ?2?1-mediated pathway. Interestingly, HPV16 E6 also interacted, via its basic nuclear localization signal (NLS) located at the C terminus, with both Kap ?1 and Kap ?2 import receptors. Binding of RanGTP to these Kap ?s inhibited their interaction with HPV16 E6 NLS. In agreement with these binding data, nuclear import of the HPV16 E6 oncoprotein in digitonin-permeabilized HeLa cells could be mediated by either Kap ?1 or Kap ?2. Nuclear import via these pathways required RanGDP and was independent of GTP hydrolysis by Ran. Significantly, an E6R124G mutant had reduced nuclear import activity, and the E6 deletion mutant lacking 121KKQR124 was not imported into the nucleus. The data reveal that the HPV16 E6 oncoprotein interacts via its C-terminal NLS with several karyopherins and exploits these interactions to enter the nucleus of host cells via multiple pathways. PMID:12551970

  6. A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.

    PubMed Central

    Jousset, C; Carron, C; Boureux, A; Quang, C T; Oury, C; Dusanter-Fourt, I; Charon, M; Levin, J; Bernard, O; Ghysdael, J

    1997-01-01

    TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators. PMID:9009269

  7. Supersymmetric E$_{7(7)}$ Exceptional Field Theory

    E-print Network

    Hadi Godazgar; Mahdi Godazgar; Olaf Hohm; Hermann Nicolai; Henning Samtleben

    2014-09-05

    We give the supersymmetric extension of exceptional field theory for E$_{7(7)}$, which is based on a $(4+56)$-dimensional generalized spacetime subject to a covariant constraint. The fermions are tensors under the local Lorentz group ${\\rm SO}(1,3)\\times {\\rm SU}(8)$ and transform as scalar densities under the E$_{7(7)}$ (internal) generalized diffeomorphisms. The supersymmetry transformations are manifestly covariant under these symmetries and close, in particular, into the generalized diffeomorphisms of the 56-dimensional space. We give the fermionic field equations and prove supersymmetric invariance. We establish the consistency of these results with the recently constructed generalized geometric formulation of $D=11$ supergravity.

  8. Amino-functionalized poly(l-lactide) lamellar single crystals as a valuable substrate for delivery of HPV16-E7 tumor antigen in vaccine development

    PubMed Central

    Di Bonito, Paola; Petrone, Linda; Casini, Gabriele; Francolini, Iolanda; Ammendolia, Maria Grazia; Accardi, Luisa; Piozzi, Antonella; D’Ilario, Lucio; Martinelli, Andrea

    2015-01-01

    Background Poly(l-lactide) (PLLA) is a biodegradable polymer currently used in many biomedical applications, including the production of resorbable surgical devices, porous scaffolds for tissue engineering, nanoparticles and microparticles for the controlled release of drugs or antigens. The surfaces of lamellar PLLA single crystals (PLLAsc) were provided with amino groups by reaction with a multifunctional amine and used to adsorb an Escherichia coli-produced human papillomavirus (HPV)16-E7 protein to evaluate its possible use in antigen delivery for vaccine development. Methods PLLA single crystals were made to react with tetraethylenepentamine to obtain amino-functionalized PLLA single crystals (APLLAsc). Pristine and amino-functionalized PLLAsc showed a two-dimensional microsized and one-dimensional nanosized lamellar morphology, with a lateral dimension of about 15–20 ?m, a thickness of about 12 nm, and a surface specific area of about 130 m2/g. Both particles were characterized and loaded with HPV16-E7 before being administered to C57BL/6 mice for immunogenicity studies. The E7-specific humoral-mediated and cell-mediated immune response as well as tumor protective immunity were analyzed in mice challenged with TC-1 cancer cells. Results Pristine and amino-functionalized PLLAsc adsorbed similar amounts of E7 protein, but in protein-release experiments E7-PLLAsc released a higher amount of protein than E7-APLLAsc. When the complexes were dried for observation by scanning electron microscopy, both samples showed a compact layer, but E7-APLLAsc showed greater roughness than E7-PLLAsc. Immunization experiments in mice showed that E7-APLLAsc induced a stronger E7-specific immune response when compared with E7-PLLAsc. Immunoglobulin G isotyping and interferon gamma analysis suggested a mixed Th1/Th2 immune response in both E7-PLLAsc-immunized and E7-APLLAsc-immunized mice. However, only the mice receiving E7-APLLAsc were fully protected from TC-1 tumor growth after three doses of vaccine. Conclusion Our results show that APLLA single crystals improve the immunogenicity of HPV16-E7 and indicate that E7-APLLAsc could be used for development of an HPV16 therapeutic vaccine against HPV16-related tumors.

  9. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2

    PubMed Central

    Bueren-Calabuig, Juan A.; Michel, Julien

    2015-01-01

    Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2. PMID:26046940

  10. N=8 Counterterms and E7(7) Current Conservation

    E-print Network

    Renata Kallosh

    2011-04-28

    We examine conservation of the E7(7) Noether-Gaillard-Zumino current in the presence of N=8 supergravity counterterms using the momentum space helicity formalism, which significantly simplifies the calculations. The main result is that the 4-point counterterms at any loop order L are forbidden by the E7(7) current conservation identity. We also clarify the relation between linearized and full non-linear superinvariants as candidate counterterms. This enables us to show that all n-point counterterms at L=7, 8 are forbidden since they provide a non-linear completions of the 4-point ones. This supports and exemplifies our general proof in arXiv:1103.4115 of perturbative UV finiteness of N=8 supergravity.

  11. E. 7th Ave. E. 6th Ave.

    E-print Network

    Howat, Ian M.

    E. 7th Ave. E. 6th Ave. CourtlandAve. SectionAlley FrancesPl. E. 6th Ave. E. 6th Ave.E. 6th Ave. SummitSt. N.4thSt. IndianolaAve. IndianolaAve. IndianolaAve.IndianolaAve. IndianolaAve. E. 13th Ave. E. 15th Ave. E. 17th Ave. E. 16th Ave. E. Woodru Ave. E. 17th Ave. E. 18th Ave. Frambes Ave. N

  12. Oxymatrine Downregulates HPV16E7 Expression and Inhibits Cell Proliferation in Laryngeal Squamous Cell Carcinoma Hep-2 Cells In Vitro

    PubMed Central

    Ying, Xin-Jiang; Jin, Bin; Chen, Xin-Wei; Xie, Jin; Xu, Hong-Ming; Dong, Pin

    2015-01-01

    Objective. To investigate the possible mechanisms of oxymatrine's role in anti laryngeal squamous cell carcinoma. Methods. We examined the effects of oxymatrine on the proliferation, cell cycle phase distribution, apoptosis, and the protein and mRNA expression levels of HPV16E7 gene in laryngeal carcinoma Hep-2 cells in vitro. The HPV16E7 siRNA inhibition was also done to confirm the effect of downregulating HPV16E7 on the proliferation in Hep-2 cells. Results. Oxymatrine significantly inhibited the growth and proliferation of Hep-2 cells in a dose-dependence and time-dependence manner. Oxymatrine blocked Hep-2 cells in G0/G1 phase, resulting in an obvious accumulation of G0/G1 phase cells while decreasing S phase cells. Oxymatrine induced apoptosis of Hep-2 cells, whose apoptotic rate amounted to about 42% after treatment with 7?mg/mL oxymatrine for 72?h. Oxymatrine also downregulated the expression of HPV16E7 gene, as determined by the western blotting and reverse transcription-polymerase chain reaction analysis. Knockdown of HPV16E7 effectively inhibited the proliferation of Hep-2 cells. Conclusions. Oxymatrine inhibits the proliferation and induces apoptosis of laryngeal carcinoma Hep-2 cells, which might be mediated by a significant cell cycle arrest in G0/G1 phase and downregulation of HPV16E7 gene. Oxymatrine is considered to be a likely preventive and curative candidate for laryngeal cancer. PMID:25811021

  13. The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

    Microsoft Academic Search

    Stephen J. Ralph; Sara Rodríguez-Enríquez; Jiri Neuzil; Emma Saavedra; Rafael Moreno-Sánchez

    2010-01-01

    The role of oncoproteins and tumor suppressor proteins in promoting the malignant transformation of mammalian cells by affecting properties such as proliferative signalling, cell cycle regulation and altered adhesion is well established. Chemicals, viruses and radiation are also generally accepted as agents that commonly induce mutations in the genes encoding these cancer-causing proteins, thereby giving rise to cancer. However, more

  14. Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor-Activating Mutations

    Microsoft Academic Search

    Seiji Yano; Wei Wang; Kunio Matsumoto; Haruko Sakurama; Takahiro Nakamura; Hirokazu Ogino; Soji Kakiuchi; Masaki Hanibuchi; Yasuhiko Nishioka; Hisanori Uehara; Tetsuya Mitsudomi; Yasushi Yatabe; Toshikazu Nakamura; Saburo Sone

    Lung cancer with epidermal growth factor receptor (EGFR)- activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma

  15. A novel dithiocarbamate derivative induces cell apoptosis through p53-dependent intrinsic pathway and suppresses the expression of the E6 oncogene of human papillomavirus 18 in HeLa cells.

    PubMed

    Li, Yanhong; Qi, Hongxue; Li, Xiaobo; Hou, Xueling; Lu, Xueying; Xiao, Xiangwen

    2015-06-01

    Dithiocarbamates (DTCs) exhibit a broad spectrum of antitumor activities, however, their molecular mechanisms of antitumor have not yet been elucidated. Previously, we have synthesized a series of novel dithiocarbamate derivatives. These DTCs were examined for cytotoxic activities against five human cancer cell lines. In this study, one of dithiocarbamate (DTC1) with higher potential for HeLa cells was chosen to investigate molecular mechanisms for its anti-tumor activities. DTC1 could inhibit proliferation, and highly induce apoptosis in HeLa cells by activating caspase-3, -6 and -9; moreover, activities of caspase-3, -6 and -9 were inhibited by pan-caspase inhibitor, Z-VAD-FMK. Furthermore, DTC1 decreased the levels of Bcl-2 and Bcl-xL, and increased expression of cytosol cytochrome c, Bak, Bax and p53 in a time-dependent manner but had no effect on the level of Rb. It was shown that DTC1 induced HeLa cells apoptosis through a p53-dependent pathway as tested by the wild type p53 inhibitor, pifithrin-?. Additionally, the relative expression of E6 and E7 were evaluated in HPV18-positive (HeLa cells) by real-time PCR and western blotting. The results firstly demonstrated that DTC1 suppressed both expression of E6 mRNA and E6 oncoprotein, but had no effect on the expression of E7 mRNA and protein in HPV18. Our results suggested that DTC1 may serve as novel chemotherapeutic agents in the treatment of cervical cancer and potential anti-HPV virus candidates that merit further studies. PMID:25772545

  16. HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial

    PubMed Central

    2013-01-01

    Background Human papilloma virus type 16 (HPV16)-induced gynecological cancers, in particular cervical cancers, are found in many women worldwide. The HPV16 encoded oncoproteins E6 and E7 are tumor-specific targets for the adaptive immune system permitting the development of an HPV16-synthetic long peptide (SLP) vaccine with an excellent treatment profile in animal models. Here, we determined the toxicity, safety, immunogenicity and efficacy of the HPV16 SLP vaccine in patients with advanced or recurrent HPV16-induced gynecological carcinoma. Methods Patients with HPV16-positive advanced or recurrent gynecological carcinoma (n?=?20) were subcutaneously vaccinated with an HPV16-SLP vaccine consisting of a mix of 13 HPV16 E6 and HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant. The primary endpoints were safety, toxicity and tumor regression as determined by RECIST. In addition, the vaccine-induced T-cell response was assessed by proliferation and associated cytokine production as well as IFN?-ELISPOT. Results No systemic toxicity beyond CTCAE grade II was observed. In a few patients transient flu-like symptoms were observed. In 9 out of 16 tested patients vaccine-induced HPV16-specific proliferative responses were detected which were associated with the production of IFN?, TNF?, IL-5 and/or IL-10. ELISPOT analysis revealed a vaccine-induced immune response in 11 of the 13 tested patients. The capacity to respond to the vaccine was positively correlated to the patient’s immune status as reflected by their response to common recall antigens at the start of the trial. Median survival was 12.6 ± 9.1?months. No regression of tumors was observed among the 12 evaluable patients. Nineteen patients died of progressive disease. Conclusions The HPV16-SLP vaccine was well tolerated and induced a broad IFN?-associated T-cell response in patients with advanced or recurrent HPV16-induced gynecological carcinoma but neither induced tumor regression nor prevented progressive disease. We, therefore, plan to use this vaccine in combination with chemotherapy and immunomodulation. PMID:23557172

  17. MPG-based nanoparticle: An efficient delivery system for enhancing the potency of DNA vaccine expressing HPV16E7.

    PubMed

    Saleh, Tayebeh; Bolhassani, Azam; Shojaosadati, Seyed Abbas; Aghasadeghi, Mohammad Reza

    2015-06-22

    DNA vaccines against human papillomavirus (HPV) type 16 have not been successful in clinical trials, due to the lack of an appropriate delivery system. In this study, a peptide-based gene delivery system, MPG, which forms stable non-covalent nanoparticles with nucleic acids, was used for in vitro and in vivo delivery of HPV16 E7 DNA as a model antigen. The results demonstrated that at Nitrogen/Phosphate (N/P) ratio over 10:1, this peptide can effectively condense plasmid DNA into stable nanoparticles with an average size of 180-210nm and a positive surface charge. The transfection efficiency of MPG-based nanoparticles was shown to be comparable with Polyethyleneimine (PEI). The efficient protein expression detected by western blotting and flow cytometry supports the potential of MPG-based nanoparticles as a potent delivery system in DNA vaccine formulations. Immunization with MPG/E7DNA nanoparticles at an N/P ratio of 10:1 induced a stronger Th1 cellular immune response with a predominant interferon-? (IFN-?) profile than those induced by E7DNA alone in a murine tumor model. These findings suggest that MPG peptide as a novel gene delivery system could have promising applications in improving HPV therapeutic vaccines. PMID:26001433

  18. The aqueous extract of Ficus religiosa induces cell cycle arrest in human cervical cancer cell lines SiHa (HPV-16 Positive) and apoptosis in HeLa (HPV-18 positive).

    PubMed

    Choudhari, Amit S; Suryavanshi, Snehal A; Kaul-Ghanekar, Ruchika

    2013-01-01

    Natural products are being extensively explored for their potential to prevent as well as treat cancer due to their ability to target multiple molecular pathways. Ficus religiosa has been shown to exert diverse biological activities including apoptosis in breast cancer cell lines. In the present study, we report the anti-neoplastic potential of aqueous extract of F. religiosa (FRaq) bark in human cervical cancer cell lines, SiHa and HeLa. FRaq altered the growth kinetics of SiHa (HPV-16 positive) and HeLa (HPV-18 positive) cells in a dose-dependent manner. It blocked the cell cycle progression at G1/S phase in SiHa that was characterized by an increase in the expression of p53, p21 and pRb proteins with a simultaneous decrease in the expression of phospho Rb (ppRb) protein. On the other hand, in HeLa, FRaq induced apoptosis through an increase in intracellular Ca(2+) leading to loss of mitochondrial membrane potential, release of cytochrome-c and increase in the expression of caspase-3. Moreover, FRaq reduced the migration as well as invasion capability of both the cervical cancer cell lines accompanied with downregulation of MMP-2 and Her-2 expression. Interestingly, FRaq reduced the expression of viral oncoproteins E6 and E7 in both the cervical cancer cell lines. All these data suggest that F. religiosa could be explored for its chemopreventive potential in cervical cancer. PMID:23922932

  19. The Aqueous Extract of Ficus religiosa Induces Cell Cycle Arrest in Human Cervical Cancer Cell Lines SiHa (HPV-16 Positive) and Apoptosis in HeLa (HPV-18 Positive)

    PubMed Central

    Choudhari, Amit S.; Suryavanshi, Snehal A.; Kaul-Ghanekar, Ruchika

    2013-01-01

    Natural products are being extensively explored for their potential to prevent as well as treat cancer due to their ability to target multiple molecular pathways. Ficus religiosa has been shown to exert diverse biological activities including apoptosis in breast cancer cell lines. In the present study, we report the anti-neoplastic potential of aqueous extract of F. religiosa (FRaq) bark in human cervical cancer cell lines, SiHa and HeLa. FRaq altered the growth kinetics of SiHa (HPV-16 positive) and HeLa (HPV-18 positive) cells in a dose-dependent manner. It blocked the cell cycle progression at G1/S phase in SiHa that was characterized by an increase in the expression of p53, p21 and pRb proteins with a simultaneous decrease in the expression of phospho Rb (ppRb) protein. On the other hand, in HeLa, FRaq induced apoptosis through an increase in intracellular Ca2+ leading to loss of mitochondrial membrane potential, release of cytochrome-c and increase in the expression of caspase-3. Moreover, FRaq reduced the migration as well as invasion capability of both the cervical cancer cell lines accompanied with downregulation of MMP-2 and Her-2 expression. Interestingly, FRaq reduced the expression of viral oncoproteins E6 and E7 in both the cervical cancer cell lines. All these data suggest that F. religiosa could be explored for its chemopreventive potential in cervical cancer. PMID:23922932

  20. Characterization of the specific cleavage of ceiE7-mRNA of the bactericidal ColE7 operon.

    PubMed

    Chang, Ssu-Jean; Hsieh, Shih-Yang; Yuan, Hanna S; Chak, Kin-Fu

    2002-12-13

    Posttranscriptional control of the bactericidal ColE7 operon has been implicated by a feedback endonucleolytic cleavage of its own mRNA. The cleavage site has been located at the coding region of ceiE7, the second cistron of the ColE7 cea-cei-cel polycistronic transcript. Interestingly, Im7 protein, the translation product of ceiE7, is required for the specific cleavage. It was found that both sequence (GAUCUGAUU) flanking the cleavage site and the putative T1 stem-loop structure distal to the coding region of ceiE7 gene play a critical role for the specific cleavage of ceiE7-mRNA. Furthermore, we have verified that a di-nucleotide GG sequence located at the topmost position of the loop region of the putative stem-loop structure is essential for the specific cleavage of ceiE7-mRNA. Thus, our data reveal the existence of a novel mRNA degradative machinery for the regulation of the expression of ColE7 operon. PMID:12459183

  1. The PxDLLCxE sequence in conserved region 2 of human papilloma virus 18 protein E7 is required for E7 binding to centromere protein C.

    PubMed

    Yaginuma, Yuji; Eguchi, Ayami; Yoshimoto, Masafumi; Ogawa, Katsuhiro

    2012-01-01

    High-risk human papillomaviruses (HPVs) are etiologically linked to human cervical and oral cancers. HPV infection leads to aneuploidy, a numerical chromosomal aberration caused by dysregulation of chromosomal segregation. We found that high-risk HPV18 and HPV58 E7 proteins bind to centromere protein C (CENP-C), a component of the kinetochore that is essential for proper chromosomal segregation. Low-risk HPV4, HPV6, and HPV11 E7s do not bind to CENP-C. The PxDLLCxE sequence in conserved region 2 (CR2) of HPV18 E7 is required for E7 binding to CENP-C. Our results indicate that differences in the ability of high- and low-risk HPV E7s to bind to CENP-C reflect the different oncogenic potentials of high- and low-risk type HPVs. PMID:22890155

  2. Seminatural SUSY from $E_7$ Nonlinear Sigma Model

    E-print Network

    Keisuke Harigaya; Tsutomu T. Yanagida; Norimi Yokozaki

    2015-04-09

    We present a new focus point supersymemtry breaking scenario based on the supersymmetric $E_7$ non-linear sigma model. In this non-linear sigma model, squarks and sleptons are identified with (pseudo) Nambu-Goldstone bosons. Their masses are generated only radiatively through gauge and yukawa interactions, and they are much smaller than the gravitino and gaugino masses at a high energy scale. On the other hand, Higgs doublets belong to matter multiplets and hence may have unsuppressed supersymmetry-breaking soft masses. We consider their masses to be equal to the gravitino mass at the high energy scale, assuming the minimal Kahler potential for Higgs doublets. We show that the fine-tuning measure of the electroweak symmetry breaking scale is reduced significantly to $\\Delta=30-70$, if the ratio of the gravitino mass to the gaugino mass is around $5/4$. Also, the prospects of the discovery/exclusion of supersymmetric particles at the Large Hadron Collider and dark matter direct detection experiments are discussed.

  3. Soluble ectodomain of c-erbB-2 oncoprotein in relation to tumour stage and grade in human renal cell carcinoma.

    PubMed Central

    Rasmuson, T.; Grankvist, K.; Ljungberg, B.

    1997-01-01

    The soluble ectodomain of c-erbB-2 oncoprotein was measured using a sandwich enzyme immunoassay in sera from 184 patients with renal cell carcinoma before initiation of treatment. The median serum level was 2062 U ml(-1) (range 865-4905 U ml(-1)). Levels were unaffected by sex, age and renal function. An inverse relation between disease stage (P = 0.0017) and tumour grade (P = 0.0009) and the serum level of c-erbB-2 ectodomain was observed. Survival time for patients with serum levels above median level was significantly longer than for patients with lower levels (P = 0.003). In a multivariate analysis, c-erbB-2 oncoprotein lost its prognostic information, while tumour stage and tumour grade were identified as independent prognostic factors. PMID:9184185

  4. 1 H and 15 N resonance assignment, secondary structure and dynamic behaviour of the C-terminal domain of human papillomavirus oncoprotein E6

    Microsoft Academic Search

    Yves Nominé; Sebastian Charbonnier; Laurent Miguet; Noelle Potier; Alain Van Dorsselaer; R. Andrew Atkinson; Gilles Travé; Bruno Kieffer

    2005-01-01

    E6 is a viral oncoprotein implicated in cervical cancers, produced by human papillomaviruses (HPVs). E6 contains two putative zinc-binding domains of about 75 residues each. The difficulty in producing recombinant E6 has long hindered the obtention of structural data. Recently, we described the expression and purification of E6-C 4C\\/4S, a stable, folded mutant of the C-terminal domain of HPV16 E6.

  5. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia

    Microsoft Academic Search

    Berndt Enholm; Karri Paavonen; Ari Ristimäki; Vijay Kumar; Yuji Gunji; Juha Klefstrom; Laura Kivinen; Marikki Laiho; Birgitta Olofsson; Vladimir Joukov; Ulf Eriksson; Kari Alitalo

    1997-01-01

    The vascular endothelial growth factor (VEGF) family has recently been expanded by the isolation of two additional growth factors, VEGF-B and VEGF-C. Here we compare the regulation of steady-state levels of VEGF, VEGF-B and VEGF-C mRNAs in cultured cells by a variety of stimuli implicated in angiogenesis and endothelial cell physiology. Hypoxia, Ras oncoprotein and mutant p53 tumor suppressor, which

  6. Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation.

    PubMed

    Matta, Hittu; Mazzacurati, Lucia; Schamus, Sandra; Yang, Tianbing; Sun, Qinmiao; Chaudhary, Preet M

    2007-08-24

    Kaposi's sarcoma herpesvirus oncoprotein vFLIP K13 is a potent activator of NF-kappaB and plays a key role in viral pathogenesis. K13 contains a putative TRAF-interacting motif, which is reportedly required for its interaction with TRAF2. The K13-TRAF2 interaction is believed to be essential for the recruitment of K13 to the I-kappaB kinase (IKK) complex and for K13-induced NF-kappaB and JNK activation. In addition, TRAF3 has been reported to be required for K13-induced NF-kappaB and JNK activation. We have re-examined the role of the TRAFs in K13 signaling and report that mutations in the putative TRAF-interacting motif of K13 have no deleterious effect on its ability to interact with the IKK complex or activation of the NF-kappaB pathway. Furthermore, endogenously expressed TRAF2 and TRAF3 do not interact with K13 and play no role in K13-induced NF-kappaB activation or its interaction with the IKK complex. Finally, K13 does not activate the JNK pathway. Our results support a model in which K13 bypasses the upstream components of the tumor necrosis factor receptor signaling pathway and directly interacts with the IKK complex to selectively activate the NF-kappaB pathway without affecting the JNK pathway. Selective NF-kappaB activation by K13 might represent a novel strategy employed by the virus to promote latency. PMID:17597077

  7. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.

    PubMed

    Zhao, Bin; Wei, Xiaomu; Li, Weiquan; Udan, Ryan S; Yang, Qian; Kim, Joungmok; Xie, Joe; Ikenoue, Tsuneo; Yu, Jindan; Li, Li; Zheng, Pan; Ye, Keqiang; Chinnaiyan, Arul; Halder, Georg; Lai, Zhi-Chun; Guan, Kun-Liang

    2007-11-01

    The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact. PMID:17974916

  8. Dysregulating IRES-dependent translation contributes to over-expression of the Aurora A kinase onco-protein

    PubMed Central

    Dobson, Tara; Chen, Juan; Krushel, Les A.

    2014-01-01

    Over-expression of the oncoprotein, Aurora A kinase occurs in multiple types of carcinomas, often early during cell transformation. To identify mechanism(s) contributing to enhanced Aurora A protein expression, we examined normal human lung fibroblast and breast epithelial cells and compared them to non-tumorigenic breast (MCF10A and MCF12A) and tumorigenic breast and cervical epithelial cell lines (MCF-7 and HeLa S3, respectively). A subset of these immortalized lines (MCF10, MCF12A, and HeLa S3) exhibited increased levels of Aurora A protein, independent of tumorigenicity. The increase in Aurora A protein expression in these immortalized cells was not due to increased transcription/RNA stability, protein half-life or cap-dependent translation. Assays utilizing monocistronic and dicistronic RNA constructs revealed that the Aurora A 5? leader contains an internal ribosomal entry site (IRES), which is regulated through the cell cycle, peaking in G2/M phase. Moreover, IRES activity was increased in the immortalized cell lines in which Aurora A protein expression was also enhanced. Additional assays indicated that the increased internal initiation is specific to the Aurora A IRES and may be an early event during cancer progression. Taken together, these results identify a novel mechanism contributing to Aurora A kinase over-expression and possibly to immortalization leading to carcinogenesis. PMID:23661421

  9. Identification of Relevant Conformational Epitopes on the HER2 Oncoprotein by Using Large Fragment Phage Display (LFPD)

    PubMed Central

    Gabrielli, Federico; Salvi, Roberto; Garulli, Chiara; Kalogris, Cristina; Arima, Serena; Tardella, Luca; Monaci, Paolo; Pupa, Serenella M.; Tagliabue, Elda; Montani, Maura; Quaglino, Elena; Stramucci, Lorenzo; Curcio, Claudia

    2013-01-01

    We developed a new phage-display based approach, the Large Fragment Phage Display (LFPD), that can be used for mapping conformational epitopes on target molecules of immunological interest. LFPD uses a simplified and more effective phage-display approach in which only a limited set of larger fragments (about 100 aa in length) are expressed on the phage surface. Using the human HER2 oncoprotein as a target, we identified novel B-cell conformational epitopes. The same homologous epitopes were also detected in rat HER2 and all corresponded to the epitopes predicted by computational analysis (PEPITO software), showing that LFPD gives reproducible and accurate results. Interestingly, these newly identified HER2 epitopes seem to be crucial for an effective immune response against HER2-overexpressing breast cancers and might help discriminating between metastatic breast cancer and early breast cancer patients. Overall, the results obtained in this study demonstrated the utility of LFPD and its potential application to the detection of conformational epitopes on many other molecules of interest, as well as, the development of new and potentially more effective B-cell conformational epitopes based vaccines. PMID:23555577

  10. The oncoprotein HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote the proliferation of breast cancer cells

    SciTech Connect

    Zhang, Yingyi; Zhao, Yu; Li, Leilei; Shen, Yu; Cai, Xiaoli [Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China)] [Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China); Zhang, Xiaodong, E-mail: zhangxd@nankai.edu.cn [Department of Cancer Research, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071 (China)] [Department of Cancer Research, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071 (China); Ye, Lihong, E-mail: yelihong@nankai.edu.cn [Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China)] [Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China)

    2013-05-03

    Highlights: •HBXIP is able to upregulate the expression of PDGFB in breast cancer cells. •HBXIP serves as a coactivator of activating transcription factor Sp1. •HBXIP stimulates the PDGFB promoter via activating transcription factor Sp1. •HBXIP promotes the proliferation of breast cancer cell via upregulating PDGFB. -- Abstract: We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. Previously, we showed that HBXIP was able to activate nuclear factor-?B (NF-?B) in breast cancer cells. As an oncogene, the platelet-derived growth factor beta polypeptide (PDGFB) plays crucial roles in carcinogenesis. In the present study, we found that both HBXIP and PDGFB were highly expressed in breast cancer cell lines. Interestingly, HBXIP was able to increase transcriptional activity of NF-?B through PDGFB, suggesting that HBXIP is associated with PDGFB in the cells. Moreover, HBXIP was able to upregulate PDGFB at the levels of mRNA, protein and promoter in the cells. Then, we identified that HBXIP stimulated the promoter of PDGFB through activating transcription factor Sp1. In function, HBXIP enhanced the proliferation of breast cancer cells through PDGFB in vitro. Thus, we conclude that HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote proliferation of breast cancer cells.

  11. Characterization of the Meq oncoproteins of Marek's disease virus vaccine strain CVI988/Rispens 

    E-print Network

    Ajithdoss, Dharani K.

    2010-07-14

    bidirectional promoter. CVI-Meq protein in the context of other Md5 genes caused tumors only in 6% of chickens when compared to parental rMd5 (a very virulent strain), which induced lymphomas in 100% of chickens, (Reddy and Lupiani, unpublished data). Taking...

  12. High Incidence of HPV-Associated Head and Neck Cancers in FA Deficient Mice Is Associated with E7’s Induction of DNA Damage through Its Inactivation of Pocket Proteins

    PubMed Central

    Park, Jung Wook; Shin, Myeong-Kyun; Pitot, Henry C.; Lambert, Paul F.

    2013-01-01

    Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with ‘high-risk’ HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6’s oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7’s induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs. PMID:24086435

  13. High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins.

    PubMed

    Park, Jung Wook; Shin, Myeong-Kyun; Pitot, Henry C; Lambert, Paul F

    2013-01-01

    Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6's oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7's induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs. PMID:24086435

  14. Hypoxia-Induced Apoptosis in Human Cells with Normal p53 Status and Function, without Any Alteration in the Nuclear Protein Level

    Microsoft Academic Search

    Øystein Åmellem; Trond Stokke; Joe A. Sandvik; Lars Smedshammer; Erik O. Pettersen

    1997-01-01

    We have studied hypoxia-induced inactivation of cells from three established human cell lines with different p53 status. Hypoxia was found to induce apoptosis in cells expressing wild-type p53 (MCF-7 cells), but not in cells where p53 is either mutated (T-47D cells), or abrogated by expression of the HPV18 E6 oncoprotein (NHIK 3025 cells). Apoptosis was demonstrated by DNA fragmentation, using

  15. DNA binding-independent transcriptional activation of the vascular endothelial growth factor gene (VEGF) by the Myb oncoprotein

    SciTech Connect

    Lutwyche, Jodi K. [Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000 (Australia); Keough, Rebecca A. [Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000 (Australia)]. E-mail: rebecca.keough@adelaide.edu.au; Hunter, Julie [Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000 (Australia); Coles, Leeanne S. [Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000 (Australia); Gonda, Thomas J. [Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000 (Australia)]. E-mail: tgonda@cicr.uq.edu.au

    2006-06-16

    Myb is a key transcription factor that can regulate proliferation, differentiation, and apoptosis, predominantly in the haemopoietic system. Abnormal expression of Myb is associated with a number of cancers, both haemopoietic and non-haemopoietic. In order to better understand the role of Myb in normal and tumorigenic processes, we undertook a cDNA array screen to identify genes that are regulated by this factor. In this way, we identified the gene encoding vascular endothelial growth factor (VEGF) as being potentially regulated by the Myb oncoprotein in myeloid cells. To determine whether this was a direct effect on VEGF gene transcription, we examined the activity of the murine VEGF promoter in the presence of either wild-type (WT) or mutant forms of Myb. It was found that WT Myb was able to activate the VEGF promoter and that a minimal promoter region of 120 bp was sufficient to confer Myb responsiveness. Surprisingly, activation of the VEGF promoter was independent of DNA binding by Myb. This was shown by the use of DNA binding-defective Myb mutants and by mutagenesis of a potential Myb-binding site in the minimal promoter. Mutation of Sp1 sites within this region abolished Myb-mediated regulation of a reporter construct, suggesting that Myb DNA binding-independent activation of VEGF expression occurs via these Sp1 binding elements. Regulation of VEGF production by Myb has implications for the potential role of Myb in myeloid leukaemias and in solid tumours where VEGF may be functioning as an autocrine growth factor.

  16. An Intrinsically Disordered Region in the Proapoptotic ASPP2 Protein Binds to the Helicobacter pylori Oncoprotein CagA.

    PubMed

    Reingewertz, Tali H; Iosub-Amir, Anat; Bonsor, Daniel A; Mayer, Guy; Amartely, Hadar; Friedler, Assaf; Sundberg, Eric J

    2015-06-01

    The leading risk factor for gastric cancer in humans is infection by Helicobacter pylori strains that express and translocate the oncoprotein CagA into host epithelial cells. Once inside host cells, CagA interacts with ASPP2, which specifically stimulates p53-mediated apoptosis and reverses its pro-apoptotic function to promote ASPP2-dependent degradation of p53. The X-ray crystal structure of a complex between the N-terminal domain of CagA and a 56-residue fragment of ASPP2, of which 22 residues were resolved, was recently described. Here, we present biochemical and biophysical analyses of the interaction between the additional regions of CagA and ASPP2 potentially involved in this interaction. Using size exclusion chromatography-multiangle laser light scattering, circular dichroism, and nuclear magnetic resonance analyses, we observed that the ASPP2 region spanning residues 331-692, which was not part of the ASPP2 fragment used for crystallization, is intrinsically disordered in its unbound state. By surface plasmon resonance analysis and isothermal titration calorimetry, we found that a portion of this disordered region in ASPP2, residues 448-692, binds to the N-terminal domain of CagA. We also measured the affinity of the complex between the ASPP2 fragment composed of residues 693-918 and inclusive of the fragment used for crystallization and CagA. Additionally, we mapped the binding regions between ASPP2 and CagA using peptide arrays, demonstrating interactions between CagA and numerous peptides distributed throughout the ASPP2 protein sequence. Our results identify previously uncharacterized regions distributed throughout the protein sequence of ASPP2 as determinants of CagA binding, providing mechanistic insight into apoptosis reprogramming by CagA and potential new drug targets for H. pylori-mediated gastric cancer. PMID:25963096

  17. Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets.

    PubMed

    Knauf, Jeffrey A; Fagin, James A

    2009-04-01

    Constitutive activation of MAPK in cancer occurs through activating mutations or overexpression of upstream effectors in the pathway, primarily of genes encoding receptor tyrosine kinases, RAS and BRAF. Arguably, the evidence for MAPK activation is most compelling in thyroid cancers and in melanomas. In this review we discuss the mechanisms of tumor development by oncogenic BRAF in these two cancer cell lineages, since this kinase signals preferentially through this pathway. We describe recent information on the mediators of BRAF-induced tumor initiation and escape from senescence. In addition, we review the biochemical events implicated in cellular growth triggered by oncogenic BRAF and the determinants of oncogene addiction. The biology of thyroid cancers induced by oncogenic BRAF is quite distinct, both in humans and in mice. There is great interest in using these insights to design rational new therapies, for which it will become crucial to understand the determinants of sensitivity and resistance to compounds designed to block the pathway. In thyroid cancer, this interest is further heightened by new information on the role of activated BRAF and MAPK pathway activation in disrupting iodine transport and thyroid hormonogenesis. PMID:19231149

  18. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells.

    PubMed

    Raina, Deepak; Kosugi, Michio; Ahmad, Rehan; Panchamoorthy, Govind; Rajabi, Hasan; Alam, Maroof; Shimamura, Takeshi; Shapiro, Geoffrey I; Supko, Jeffrey; Kharbanda, Surender; Kufe, Donald

    2011-05-01

    Non-small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) ? Akt ? mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC cells and induces gene signatures that are associated with poor survival of NSCLC patients. The present results show that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor GO-203 was associated with downregulation of PI3K ? Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C both for activation of the PI3K ? Akt pathway and for survival. PMID:21421804

  19. Protein arginine methyltransferase 5 is a key regulator of the MYCN oncoprotein in neuroblastoma cells

    PubMed Central

    Park, Ji Hyun; Szemes, Marianna; Vieira, Gabriella Cunha; Melegh, Zsombor; Malik, Sally; Heesom, Kate J.; Von Wallwitz-Freitas, Laura; Greenhough, Alexander; Brown, Keith W.; Zheng, Y. George; Catchpoole, Daniel; Deery, Michael J.; Malik, Karim

    2015-01-01

    Approximately half of poor prognosis neuroblastomas (NBs) are characterized by pathognomonic MYCN gene amplification and MYCN over-expression. Here we present data showing that short-interfering RNA mediated depletion of the protein arginine methyltransferase 5 (PRMT5) in cell-lines representative of NBs with MYCN gene amplification leads to greatly impaired growth and apoptosis. Growth suppression is not apparent in the MYCN-negative SH-SY5Y NB cell-line, or in two immortalized human fibroblast cell-lines. Immunoblotting of NB cell-lines shows that high PRMT5 expression is strongly associated with MYCN-amplification (P < 0.004, Mann–Whitney U-test) and immunohistochemical analysis of primary NBs reveals that whilst PRMT5 protein is ubiquitously expressed in the cytoplasm of most cells, MYCN-amplified tumours exhibit pronounced nuclear PRMT5 staining. PRMT5 knockdown in MYCN-overexpressing cells, including the SHEP-21N cell-line with inducible MYCN expression leads to a dramatic decrease in MYCN protein and MYCN-associated cell-death in SHEP-21N cells. Quantitative gene expression analysis and cycloheximide chase experiments suggest that PRMT5 regulates MYCN at a post-transcriptional level. Reciprocal co-immunoprecipitation experiments demonstrated that endogenous PRMT5 and MYCN interact in both SK-N-BE(2)C and NGP cell lines. By using liquid chromatography – tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated MYCN protein, we identified several potential sites of arginine dimethylation on the MYCN protein. Together our studies implicate PRMT5 in a novel mode of MYCN post-translational regulation and suggest PRMT5 plays a major role in NB tumorigenesis. Small-molecule inhibitors of PRMT5 may therefore represent a novel therapeutic strategy for neuroblastoma and other cancers driven by the MYCN oncogene. PMID:25475372

  20. Protein arginine methyltransferase 5 is a key regulator of the MYCN oncoprotein in neuroblastoma cells.

    PubMed

    Park, Ji Hyun; Szemes, Marianna; Vieira, Gabriella Cunha; Melegh, Zsombor; Malik, Sally; Heesom, Kate J; Von Wallwitz-Freitas, Laura; Greenhough, Alexander; Brown, Keith W; Zheng, Y George; Catchpoole, Daniel; Deery, Michael J; Malik, Karim

    2015-03-01

    Approximately half of poor prognosis neuroblastomas (NBs) are characterized by pathognomonic MYCN gene amplification and MYCN over-expression. Here we present data showing that short-interfering RNA mediated depletion of the protein arginine methyltransferase 5 (PRMT5) in cell-lines representative of NBs with MYCN gene amplification leads to greatly impaired growth and apoptosis. Growth suppression is not apparent in the MYCN-negative SH-SY5Y NB cell-line, or in two immortalized human fibroblast cell-lines. Immunoblotting of NB cell-lines shows that high PRMT5 expression is strongly associated with MYCN-amplification (P < 0.004, Mann-Whitney U-test) and immunohistochemical analysis of primary NBs reveals that whilst PRMT5 protein is ubiquitously expressed in the cytoplasm of most cells, MYCN-amplified tumours exhibit pronounced nuclear PRMT5 staining. PRMT5 knockdown in MYCN-overexpressing cells, including the SHEP-21N cell-line with inducible MYCN expression leads to a dramatic decrease in MYCN protein and MYCN-associated cell-death in SHEP-21N cells. Quantitative gene expression analysis and cycloheximide chase experiments suggest that PRMT5 regulates MYCN at a post-transcriptional level. Reciprocal co-immunoprecipitation experiments demonstrated that endogenous PRMT5 and MYCN interact in both SK-N-BE(2)C and NGP cell lines. By using liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated MYCN protein, we identified several potential sites of arginine dimethylation on the MYCN protein. Together our studies implicate PRMT5 in a novel mode of MYCN post-translational regulation and suggest PRMT5 plays a major role in NB tumorigenesis. Small-molecule inhibitors of PRMT5 may therefore represent a novel therapeutic strategy for neuroblastoma and other cancers driven by the MYCN oncogene. PMID:25475372

  1. Targeting Epstein–Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy

    PubMed Central

    Xiao, L; Hu, Z-y; Dong, X; Tan, Z; Li, W; Tang, M; Chen, L; Yang, L; Tao, Y; Jiang, Y; Li, J; Yi, B; Li, B; Fan, S; You, S; Deng, X; Hu, F; Feng, L; Bode, A M; Dong, Z; Sun, L-q; Cao, Y

    2014-01-01

    Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers. PMID:24662831

  2. Radiosensitization of Oropharyngeal Squamous Cell Carcinoma Cells by Human Papillomavirus 16 Oncoprotein E6*I

    SciTech Connect

    Pang, Ervinna [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Delic, Naomi C. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia); Hong, Angela; Zhang Mei [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Department of Radiation Oncology, Royal Prince Alfred Hospital, NSW (Australia); Rose, Barbara R. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Lyons, J. Guy, E-mail: guy.lyons@sydney.edu.a [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia)

    2011-03-01

    Purpose: Patients with oropharyngeal squamous cell carcinoma (OSCC) whose disease is associated with high-risk human papillomavirus (HPV) infection have a significantly better outcome than those with HPV-negative disease, but the reasons for the better outcome are not known. We postulated that they might relate to an ability of HPV proteins to confer a better response to radiotherapy, a commonly used treatment for OSCC. Methods and Materials: We stably expressed the specific splicing-derived isoforms, E6*I and E6*II, or the entire E6 open reading frame (E6total), which gives rise to both full length and E6*I isoforms, in OSCC cell lines. Radiation resistance was measured in clonogenicity assays, p53 activity was measured using transfected reporter genes, and flow cytometry was used to analyze cell cycle and apoptosis. Results: E6*I and E6total sensitized the OSCC cells to irradiation, E6*I giving the greatest degree of radiosensitization (approximately eightfold lower surviving cell fraction at 10 Gy), whereas E6*II had no effect. In contrast to radiosensitivity, E6*I was a weaker inhibitor than E6total of tumor suppressor p53 transactivator activity in the same cells. Flow cytometric analyses showed that irradiated E6*I expressing cells had a much higher G2M:G1 ratio than control cells, indicating that, after G2, cells were diverted from the cell cycle to programmed cell death. Conclusion: This study supports a role for E6*I in the enhanced responsiveness of HPV-positive oropharyngeal carcinomas to p53-independent radiation-induced death.

  3. High-affinity interaction of poly(ADP-ribose) and the human DEK oncoprotein depends upon chain length.

    PubMed

    Fahrer, Jörg; Popp, Oliver; Malanga, Maria; Beneke, Sascha; Markovitz, David M; Ferrando-May, Elisa; Bürkle, Alexander; Kappes, Ferdinand

    2010-08-24

    Poly(ADP-ribose) polymerase-1 (PARP-1) is a molecular DNA damage sensor that catalyzes the synthesis of the complex biopolymer poly(ADP-ribose) (PAR) under consumption of NAD(+). PAR engages in fundamental cellular processes such as DNA metabolism and transcription and interacts noncovalently with specific binding proteins involved in DNA repair and regulation of chromatin structure. A factor implicated in DNA repair and chromatin organization is the DEK oncoprotein, an abundant and conserved constituent of metazoan chromatin, and the only member of its protein class. We have recently demonstrated that DEK, under stress conditions, is covalently modified with PAR by PARP-1, leading to a partial release of DEK into the cytoplasm. Additionally, we have also observed a noncovalent interaction between DEK and PAR, which we detail here. Using sequence alignment, we identify three functional PAR-binding sites in the DEK primary sequence and confirm their functionality in PAR binding studies. Furthermore, we show that the noncovalent binding to DEK is dependent on PAR chain length as revealed by an overlay blot technique and a PAR electrophoretic mobility shift assay. Intriguingly, DEK promotes the formation of a defined complex with a 54mer PAR (K(D) = 6 x 10(-8) M), whereas no specific interaction is detected with a short PAR chain (18mer). In stark contrast to covalent poly(ADP-ribosyl)ation of DEK, the noncovalent interaction does not affect the overall ability of DEK to bind to DNA. Instead the noncovalent interaction interferes with subsequent DNA-dependent multimerization activities of DEK, as seen in South-Western, electrophoretic mobility shift, topology, and aggregation assays. In particular, noncovalent attachment of PAR to DEK promotes the formation of DEK-DEK complexes by competing with DNA binding. This was seen by the reduced affinity of PAR-bound DEK for DNA templates in solution. Taken together, our findings deepen the molecular understanding of the DEK-PAR interplay and support the existence of a cellular "PAR code" represented by PAR chain length. PMID:20669926

  4. 17 CFR 240.14e-7 - Unlawful tender offer practices in connection with roll-ups.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...false Unlawful tender offer practices in connection with roll-ups. 240.14e-7 Section 240.14e-7 Commodity and Securities...14e-7 Unlawful tender offer practices in connection with roll-ups. In order to implement section 14(h) of the Act (15...

  5. Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein

    PubMed Central

    Peloponese, Jean-Marie; Haller, Kerstin; Miyazato, Akiko; Jeang, Kuan-Teh

    2005-01-01

    Human T cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T cell leukemia. The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. Because adult T cell leukemia like many other human cancers is a disease of genomic instability with frequent gains and losses of chromosomes, to understand this disease it is important to comprehend how HTLV-1 engenders aneuploidy in host cells. In this regard, loss of cell cycle checkpoints permits tolerance of aneuploidy but does not explain how aneuploidy is created. We show here that HTLV-1 Tax causes abnormal centrosome fragmentation in the mitotic phase of the cell cycle. We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes. PMID:16365316

  6. Oncoprotein protein kinase

    DOEpatents

    Karin, Michael (San Diego, CA); Hibi, Masahiko (San Diego, CA); Lin, Anning (La Jolla, CA)

    2002-01-29

    The present invention provides an isolated polynucleotide encoding a c-Jun peptide consisting of about amino acid residues 33 to 79 as set fort in SEQ ID NO: 10 or conservative variations thereof. The invention also provides a method for producing a peptide of SEQ ID NO:1 comprising (a) culturing a host cell containing a polynucleotide encoding a c-Jun peptide consisting of about amino acid residues 33 to 79 as set forth in SEQ ID NO: 10 under conditions which allow expression of the polynucleotide; and (b) obtaining the peptide of SEQ ID NO:1.

  7. Minimal representations of E6, E7, and E8 and the generalized Capelli identity.

    PubMed Central

    Brylinski, R; Kostant, B

    1994-01-01

    We explicitly construct, in a uniform fashion, the (unique) minimal and spherical representation pi0 of the split real Lie group of exceptional type E6, E7, or E8. We obtain several algebraic and analytic results about pi0. PMID:11607467

  8. The human papillomavirus18 E7 protein inhibits CENP-C binding to ?-satellite DNA.

    PubMed

    Yaginuma, Yuji; Yoshimoto, Masafumi; Eguchi, Ayami; Tokuda, Aoi; Takahashi, Shoko

    2015-07-01

    Human papillomavirus (HPV) infection leads to aneuploidy, a numerical chromosomal aberration that is caused by dysregulation of chromosomal segregation. We previously found that the E7 proteins of high-risk HPVs, but not of low-risk HPVs, could bind to centromere protein-C (CENP-C). In this study, we first found that CENP-C could bind centromere ?-satellite DNAs using ChIP analysis and HA-tagged CENP-C/nuc transfected 293T cells. We then investigated if HA-CENP-C/nuc binding to ?-satellite DNAs was affected by the E7 proteins of high- or low-risk HPVs. We found that transfection of the FLAG tagged HPV18 E7 inhibited the binding of HA-CENP-C/nuc to ?-satellite DNAs. This finding was confirmed in HeLa S3 cells transfected with siRNA targeted to HPV18 E7 expression. We therefore speculate that altered function of kinetochores as a result of inhibition of CENP-C and ?-satellite DNAs binding may be associated with the chromosomal abnormalities observed in HPV18-positive cancers. PMID:25997930

  9. Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells

    PubMed Central

    2011-01-01

    Background- Specific types of high risk Human papillomaviruses (HR-HPVs) particularly, HPV types 16 and 18 cause cervical cancer and while the two recently developed vaccines against these HPV types are prophylactic in nature, therapeutic options for treatment and management of already existing HPV infection are not available as yet. Because transcription factor, Activator Protein-1 (AP-1) plays a central role in HPV-mediated cervical carcinogenesis, we explored the possibility of its therapeutic targeting by berberine, a natural alkaloid derived from a medicinal plant species, Berberis which has been shown to possess anti-inflammatory and anti-cancer properties with no known toxicity; however, the effect of berberine against HPV has not been elucidated. Results- We studied the effect of berberine on HPV16-positive cervical cancer cell line, SiHa and HPV18-positive cervical cancer cell line, HeLa using electrophoretic mobility gel shift assays, western and northern blotting which showed that berberine could selectively inhibit constitutively activated AP-1 in a dose- and time-dependent manner and downregulates HPV oncogenes expression. Inhibition of AP-1 was also accompanied by changes in the composition of their DNA-binding complex. Berberine specifically downregulated expression of oncogenic c-Fos which was also absent in the AP-1 binding complex. Treatment with berberine resulted in repression of E6 and E7 levels and concomitant increase in p53 and Rb expression in both cell types. Berberine also suppressed expression of telomerase protein, hTERT, which translated into growth inhibition of cervical cancer cells. Interestingly, a higher concentration of berberine was found to reduce the cell viability through mitochondria-mediated pathway and induce apoptosis by activating caspase-3. Conclusion- These results indicate that berberine can effectively target both the host and viral factors responsible for development of cervical cancer through inhibition of AP-1 and blocking viral oncoproteins E6 and E7 expression. Inhibition of AP-1 activity by berberine may be one of the mechanisms responsible for the anti-HPV effect of berberine. We propose that berberine is a potentially promising compound for the treatment of cervical cancer infected with HPV. PMID:21496227

  10. Examination of the pRb-Dependent and pRb-Independent Functions of E7 In Vivo

    Microsoft Academic Search

    Scott Balsitis; Fred Dick; Denis Lee; Linda Farrell; R. Katherine Hyde; Anne E. Griep; Nicholas Dyson; Paul F. Lambert

    2005-01-01

    High-risk human papillomaviruses encode two oncogenes, E6 and E7, expressed in nearly all cervical cancers. Although E7 protein is best known for its ability to inactivate the retinoblastoma tumor suppressor protein, pRb, many other activities for E7 have been proposed in in vitro studies. Herein, we describe studies that allowed us to define unambiguously the pRb-dependent and -independent activities of

  11. Oncoprotein HCCR-1 expression in breast cancer is well correlated with known breast cancer prognostic factors including the HER2 overexpression, p53 mutation, and ER\\/PR status

    Microsoft Academic Search

    Seon-Ah Ha; Youn Soo Lee; Seung Min Shin; Hyun Kee Kim; Sanghee Kim; Hong Namkoong; Hae Joo Kim; Sang Min Jung; Yu Sun Lee; Yeun Jun Chung; Sang Seol Jung; Jin Woo Kim

    2009-01-01

    BACKGROUND: Oncoprotein HCCR-1 functions as a negative regulator of the p53 and contributes breast tumorigenesis. The serum HCCR-1 assay is useful in diagnosing breast cancer and mice transgenic for HCCR developed breast cancers. But it is unknown how HCCR-1 contributes to human breast tumorigenesis. METHODS: Oncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer

  12. Expression of mucosa-related integrin ?E?7 on alveolar T cells in interstitial lung diseases

    PubMed Central

    Lohmeyer, J; Friedrich, J; Grimminger, F; Maus, U; Tenter, R; Morr, H; Velcovsky, H G; Seeger, W; Rosseau, S

    1999-01-01

    The expression of ?E?7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated ?E?7 expression patterns on cells accounting for lymphocytic alveolitis in interstitial lung disease (ILD), ?E expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF; n = 18), hypersensitivity pneumonitis (HP; n = 20) and sarcoidosis (n = 44) in comparison with healthy controls (n = 15). In both healthy individuals and all patient groups the proportion of ?E-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed ?E. Absolute alveolar CD8+?E+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of ?E-bearing CD4+ cells in BALF were significantly elevated in IPF (74.0 ± 2.7%) and HP (70.0 ± 2.4%) compared with normals (30.0 ± 1.8%) (mean ± s.e.m.; P < 0.01). In sarcoidosis, the ?E expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I (14.3 ± 1.5%), but increased proportions in stages II (50.0 ± 3.8%) and III (64.0 ± 4.8%). Correlations between common markers of T cell activation or BALF transforming growth factor-beta (TGF-?) bioactivity and ?E expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express ?E?7 and that distinct patterns of ?E?7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung. PMID:10337028

  13. Cervical response to vaccination against HPV16 E7 in case of severe dysplasia

    Microsoft Academic Search

    Ph. Simon; F. Buxant; S. Hallez; A. Burny; I. Fayt; V. Anaf; J. C. Noël

    2003-01-01

    Objective: To evaluate the tolerance to vaccination against human papillomavirus (HPV)16 E7 (in SB adjuvant ASO2B) and its histological and immunohistological effects on HPV16 associated high-grade cervical dysplasias associated with HPV16. Study design: Five patients with histologically demonstrated severe cervical dysplasia (CIN3) HPV16 positive were injected three times before conization was performed 2 months after the first injection. We studied

  14. Tyrosine B10 triggers a heme propionate hydrogen bonding network loop with glutamine E7 moiety

    SciTech Connect

    Ramos-Santana, Brenda J., E-mail: brenda.ramos@upr.edu [Department of Chemistry, University of Puerto Rico, Mayagueez Campus, P.O. Box 9019, Mayagueez 00681-9019 (Puerto Rico); Lopez-Garriga, Juan, E-mail: juan.lopez16@upr.edu [Department of Chemistry, University of Puerto Rico, Mayagueez Campus, P.O. Box 9019, Mayagueez 00681-9019 (Puerto Rico)] [Department of Chemistry, University of Puerto Rico, Mayagueez Campus, P.O. Box 9019, Mayagueez 00681-9019 (Puerto Rico)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer H-bonding network loop by PheB10Tyr mutation is proposed. Black-Right-Pointing-Pointer The propionate group H-bonding network restricted the flexibility of the heme. Black-Right-Pointing-Pointer The hydrogen bonding interaction modulates the electron density of the iron. Black-Right-Pointing-Pointer Propionate H-bonding network loop explains the heme-ligand stabilization. -- Abstract: Propionates, as peripheral groups of the heme active center in hemeproteins have been described to contribute in the modulation of heme reactivity and ligand selection. These electronic characteristics prompted the question of whether the presence of hydrogen bonding networks between propionates and distal amino acids present in the heme ligand moiety can modulate physiological relevant events, like ligand binding association and dissociation activities. Here, the role of these networks was evaluated by NMR spectroscopy using the hemoglobin I PheB10Tyr mutant from Lucina pectinata as model for TyrB10 and GlnE7 hemeproteins. {sup 1}H-NMR results for the rHbICN PheB10Tyr derivative showed chemical shifts of TyrB10 OH{eta} at 31.00 ppm, GlnE7 N{sub {epsilon}1}H/N{sub {epsilon}2}H at 10.66 ppm/-3.27 ppm, and PheE11 C{sub {delta}}H at 11.75 ppm, indicating the presence of a crowded, collapsed, and constrained distal pocket. Strong dipolar contacts and inter-residues crosspeaks between GlnE7/6-propionate group, GlnE7/TyrB10 and TyrB10/CN suggest that this hydrogen bonding network loop between GlnE7, TyrB10, 6-propionate group, and the heme ligand contribute significantly to the modulation of the heme iron electron density as well as the ligand stabilization mechanism. Therefore, the network loop presented here support the fact that the electron withdrawing character of the hydrogen bonding is controlled by the interaction of the propionates and the nearby electronic environments contributing to the modulation of the heme electron density state. Thus, we hypothesize that in hemeproteins with similar electrostatic environment the flexibility of the heme-6-propionate promotes a hydrogen bonding network loop between the 6-propionate, the heme ligand and nearby amino acids, tailoring in this way the electron density in the heme-ligand moiety.

  15. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax.

    PubMed

    Mann, Melanie C; Strobel, Sarah; Fleckenstein, Bernhard; Kress, Andrea K

    2014-09-01

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. PMID:25058508

  16. The HBx Oncoprotein of Hepatitis B Virus Deregulates the Cell Cycle by Promoting the Intracellular Accumulation and Re-Compartmentalization of the Cellular Deubiquitinase USP37

    PubMed Central

    Saxena, Nehul; Kumar, Vijay

    2014-01-01

    The HBx oncoprotein of hepatitis B Virus has been accredited as one of the protagonists in driving hepatocarcinogenesis. HBx exerts its influence over the cell cycle progression by potentiating the activity of cyclin A/E-CDK2 complex, the Cyclin A partner of which is a well-known target of cellular deubiquitinase USP37. In the present study, we observed the intracellular accumulation of cyclin A and USP37 proteins under the HBx microenvironment. Flow cytometry analysis of the HBx-expressing cells showed deregulation of cell cycle apparently due to the enhanced gene expression and stabilization of USP37 protein and deubiquitination of Cyclin A by USP37. Our co-immunoprecipitation and confocal microscopic studies suggested a direct interaction between USP37 and HBx. This interaction promoted the translocation of USP37 outside the nucleus and prevented its association and ubiquitination by E3 ubiquitin ligases - APC/CDH1 and SCF/?-TrCP. Thus, HBx seems to control the cell cycle progression via the cyclin A-CDK2 complex by regulating the intracellular distribution and stability of deubiquitinase USP37. PMID:25347529

  17. A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo.

    PubMed

    Shirinian, Margret; Kambris, Zakaria; Hamadeh, Lama; Grabbe, Caroline; Journo, Chloé; Mahieux, Renaud; Bazarbachi, Ali

    2015-08-01

    Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-?B. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKK?/NEMO), thus validating this new in vivo model. PMID:25995252

  18. Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16\\/18 E6E7)

    Microsoft Academic Search

    E. J Davidson; R. L Faulkner; P Sehr; M Pawlita; L. J. C Smyth; D. J Burt; A. E Tomlinson; J Hickling; H. C Kitchener; P. L Stern

    2004-01-01

    Heterologous prime-boost vaccination schedules employing TA-HPV, a vaccinia virus encoding HPV 16\\/18 E6 and E7, in combination with TA-CIN, an HPV 16 L2E6E7 fusion protein, may offer advantages over the use of either agent alone for the immunotherapy of human papillomavirus (HPV) type 16-associated vulval intraepithelial neoplasia (VIN). In the present study, 10 women with HPV 16-positive high grade VIN,

  19. Characterization of Human Ovarian Surface Epithelial Cells Immortalized by Human Papilloma Viral Oncogenes (HPV-E6E7 ORFs)

    Microsoft Academic Search

    Sai-Wah Tsao; Samuel C. Mok; Edward G. Fey; Jonathan A. Fletcher; Thomas S. K. Wan; Eng-Ching Chew; Michael G. Muto; Robert C. Knapp; Ross S. Berkowitz

    1995-01-01

    Primary human ovarian surface epithelial (HOSE) cells were immortalized by a retroviral vector (LXSN-16E6E7) expressing HPV-E6E7 open reading frames (ORF). Immortalizations of primary ovarian epithelial cells were achieved in three of three attempts. Detailed analysis was carried out in one line, HOSE 6-3, selected on the basis of its epithelial morphology. The immortalized line (HOSE 6-3) was nontumorigenic in nude

  20. Proteomic Investigation in A549 Lung Cell Line Stably Infected by HPV16E6\\/E7 Oncogenes

    Microsoft Academic Search

    Marco Ciotti; Valeria Marzano; Laura Giuliani; Marzia Nuccetelli; Simona D’Aguanno; Barbara Azzimonti; Sergio Bernardini; Carlo Federico Perno; Andrea Urbani; Cartesio Favalli; Giorgio Federici

    2009-01-01

    Background: Data have accumulated implicating the involvement of oncogenic human papillomaviruses (HPVs) in bronchial carcinogenesis. We recently described the presence of oncogenic HPV transcripts in non-small cell lung cancers. Objective: To investigate the role of oncogenic HPVs in lung carcinogenesis. Material and Methods: The lung cell line A549 stably infected with HPV16E6, HPV16E7 and HPVE6\\/E7 constructs was used to investigate

  1. Expression of the L2 and E7 genes of the human papillomavirus type 16 in female genital dysplasias.

    PubMed Central

    Auvinen, E.; Kujari, H.; Arstila, P.; Hukkanen, V.

    1992-01-01

    The expression of the E7 and L2 genes of HPV 16 was studied in benign and precancerous female genital lesions to evaluate their role in the development of dysplasias. Ninety biopsy specimens from 70 patients, selected on basis of dot blot DNA hybridization, were included in immunohistochemical and in situ hybridization analyses. In the HPV 16 DNA positive cases, L2 mRNA and E7 mRNA were detected in biopsies from 24 and 21 patients, respectively. L2 mRNA was found in eight of 16 cases of condyloma and mild dysplasia, and in 13 of 14 cases of moderate to severe dysplasia. The figures for E7 mRNA were 6/16 and 13/14, respectively. We found L2 mRNA in four of 12 normal or condylomatous specimens and E7 mRNA in only one of these. The detection rates for L2 and E7 mRNAs increased along with the severity of the lesions (P = 0.0064 and P = 0.0001, respectively). The L2 protein was found in one condyloma and in 12 dysplasias, eight of which were moderate or severe. The L2-antibody-reactive cells were localized in superficial layers of the epithelium. The detection rate for L2 mRNA and especially for E7 mRNA increased along with the histopathologic grade of the lesion. Images Figure 2 PMID:1332486

  2. ERP, a new member of the ets transcription factor/oncoprotein family: cloning, characterization, and differential expression during B-lymphocyte development.

    PubMed Central

    Lopez, M; Oettgen, P; Akbarali, Y; Dendorfer, U; Libermann, T A

    1994-01-01

    The ets gene family encodes a group of proteins which function as transcription factors under physiological conditions and, if aberrantly expressed, can cause cellular transformation. We have recently identified two regulatory elements in the murine immunoglobulin heavy-chain (IgH) enhancer, pi and microB, which exhibit striking similarity to binding sites for ets-related proteins. To identify ets-related transcriptional regulators expressed in pre-B lymphocytes that may interact with either the pi or the microB site, we have used a PCR approach with degenerate oligonucleotides encoding conserved sequences in all members of the ets family. We have cloned the gene for a new ets-related transcription factor, ERP (ets-related protein), from the murine pre-B cell line BASC 6C2 and from mouse lung tissue. The ERP protein contains a region of high homology with the ETS DNA-binding domain common to all members of the ets transcription factor/oncoprotein family. Three additional smaller regions show homology to the ELK-1 and SAP-1 genes, a subgroup of the ets gene family that interacts with the serum response factor. Full-length ERP expresses only negligible DNA-binding activity by itself. Removal of the carboxy terminus enables ERP to interact with a variety of ets-binding sites including the E74 site, the IgH enhancer pi site, and the lck promoter ets site, suggesting a carboxy-terminal negative regulatory domain. At least three ERP-related transcripts are expressed in a variety of tissues. However, within the B-cell lineage, ERP is highly expressed primarily at early stages of B-lymphocyte development, and expression declines drastically upon B-cell maturation, correlating with the enhancer activity of the IgH pi site. These data suggest that ERP might play a role in B-cell development and in IgH gene regulation. Images PMID:7909357

  3. Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells.

    PubMed

    Takachi, Takayuki; Takahashi, Masahiko; Takahashi-Yoshita, Manami; Higuchi, Masaya; Obata, Miki; Mishima, Yukio; Okuda, Shujiro; Tanaka, Yuetsu; Matsuoka, Masao; Saitoh, Akihiko; Green, Patrick L; Fujii, Masahiro

    2015-04-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-?B, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells. PMID:25613934

  4. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling.

    PubMed

    Guasparri, Ilaria; Wu, Hao; Cesarman, Ethel

    2006-01-01

    Primary effusion lymphomas (PELs) characterized by infection with the Kaposi's sarcoma herpesvirus (KSHV; also called human herpesvirus 8) depend on the expression of the viral FADD-like interleukin-1-beta-converting enzyme (FLICE)/caspase-8-inhibitory protein (vFLIP) for their survival. This effect is achieved by activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Tumour necrosis factor (TNF) receptor-associated factors (TRAFs) are direct mediators of NF-kappaB signalling by TNF family receptors and the Epstein-Barr virus oncoprotein latent membrane protein 1 and so we assessed the role of TRAFs in signalling by vFLIP. Here, we report the identification of a TRAF-interacting motif (PYQLT) in vFLIP, which is not present in other FLIP molecules. We show that vFLIP directly binds to TRAF2 in vitro and in PEL cells. TRAF2 and TRAF3 are required for induction of NF-kappaB and associated cell survival, as well as Jun amino-terminal kinase phosphorylation by vFLIP, whereas TRAF1, TRAF5 and TRAF6 are dispensable. Mutations in the P93 or Q95 amino acids within the TRAF-interacting motif of vFLIP abolish its ability to bind to TRAF2 and to signal to NF-kappaB. TRAF2, but not TRAF3, mediates the association of vFLIP with the IkappaB kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappaB, which is crucial for KSHV-associated lymphomagenesis. PMID:16311516

  5. The Oncogenic MicroRNA OncomiR-21 Overexpressed during Marek's Disease Lymphomagenesis Is Transactivated by the Viral Oncoprotein Meq

    PubMed Central

    Stik, Grégoire; Dambrine, Ginette; Pfeffer, Sébastien

    2013-01-01

    Gallid herpesvirus 2 (GaHV-2) is an oncogenic herpesvirus that causes T lymphoma in chicken. GaHV-2 encodes a basic leucine zipper (bZIP) protein of the AP-1 family, Meq. Upon formation of homo- or heterodimers with c-Jun, Meq may modulate the expression of viral and cellular genes involved in lymphomagenesis. GaHV-2 also encodes viral microRNAs (miRNAs) involved in latency and apoptosis escape. However, little is known about cellular miRNA deregulation during the development of GaHV-2-associated lymphoma. We determined the cellular miRNA expression profiles of chickens infected with a very virulent strain (RB-1B) or a vaccine strain (CVI988) or noninfected. Among the most deregulated cellular miRNAs, we focused our efforts on gga-miR-21, which is upregulated during GaHV-2 infection. We mapped the gga-miR-21 promoter to the 10th intron of the TMEM49 gene and found it to be driven by AP-1- and Ets-responsive elements. We show here that the viral oncoprotein Meq binds to this promoter, thereby transactivating gga-miR-21 expression. We confirmed that this miRNA targets chicken programmed death cell 4 (PDCD4) and promotes tumor cell growth and apoptosis escape. Finally, gga-miR-21 was overexpressed only during infection with a very virulent strain (RB-1B) and not during infection with a nononcogenic strain (CVI988), providing further evidence for its role in GaHV-2 lymphomagenesis. Our data therefore suggest an additional role for Meq in GaHV-2-mediated lymphomagenesis through the induction of miR-21 expression. PMID:23055556

  6. ERP, a new member of the ets transcription factor/oncoprotein family: cloning, characterization, and differential expression during B-lymphocyte development.

    PubMed

    Lopez, M; Oettgen, P; Akbarali, Y; Dendorfer, U; Libermann, T A

    1994-05-01

    The ets gene family encodes a group of proteins which function as transcription factors under physiological conditions and, if aberrantly expressed, can cause cellular transformation. We have recently identified two regulatory elements in the murine immunoglobulin heavy-chain (IgH) enhancer, pi and microB, which exhibit striking similarity to binding sites for ets-related proteins. To identify ets-related transcriptional regulators expressed in pre-B lymphocytes that may interact with either the pi or the microB site, we have used a PCR approach with degenerate oligonucleotides encoding conserved sequences in all members of the ets family. We have cloned the gene for a new ets-related transcription factor, ERP (ets-related protein), from the murine pre-B cell line BASC 6C2 and from mouse lung tissue. The ERP protein contains a region of high homology with the ETS DNA-binding domain common to all members of the ets transcription factor/oncoprotein family. Three additional smaller regions show homology to the ELK-1 and SAP-1 genes, a subgroup of the ets gene family that interacts with the serum response factor. Full-length ERP expresses only negligible DNA-binding activity by itself. Removal of the carboxy terminus enables ERP to interact with a variety of ets-binding sites including the E74 site, the IgH enhancer pi site, and the lck promoter ets site, suggesting a carboxy-terminal negative regulatory domain. At least three ERP-related transcripts are expressed in a variety of tissues. However, within the B-cell lineage, ERP is highly expressed primarily at early stages of B-lymphocyte development, and expression declines drastically upon B-cell maturation, correlating with the enhancer activity of the IgH pi site. These data suggest that ERP might play a role in B-cell development and in IgH gene regulation. PMID:7909357

  7. Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations.

    PubMed

    Chan, Paul K S; Zhang, Chuqing; Park, Jong-Sup; Smith-McCune, Karen K; Palefsky, Joel M; Giovannelli, Lucia; Coutlée, Francois; Hibbitts, Samantha; Konno, Ryo; Settheetham-Ishida, Wannapa; Chu, Tang-Yuan; Ferrera, Annabelle; Alejandra Picconi, María; De Marco, Federico; Woo, Yin-Ling; Raiol, Tainá; Piña-Sánchez, Patricia; Bae, Jeong-Hoon; Wong, Martin C S; Chirenje, Mike Z; Magure, Tsitsi; Moscicki, Anna-Barbara; Fiander, Alison N; Capra, Giuseppina; Young Ki, Eun; Tan, Yi; Chen, Zigui; Burk, Robert D; Chan, Martin C W; Cheung, Tak-Hong; Pim, David; Banks, Lawrence

    2013-06-01

    Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ? 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas. PMID:23136059

  8. Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells

    SciTech Connect

    Lee, Kiwon; Lee, Ah-Young [Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin 449-791 (Korea, Republic of)] [Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin 449-791 (Korea, Republic of); Kwon, Yunhee Kim [Department of Life and Nanopharmaceutical Science and Department of Biology, Kyunghee University, Seoul 130-701 (Korea, Republic of)] [Department of Life and Nanopharmaceutical Science and Department of Biology, Kyunghee University, Seoul 130-701 (Korea, Republic of); Kwon, Hyockman, E-mail: hmkwon@hufs.ac.kr [Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin 449-791 (Korea, Republic of)] [Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin 449-791 (Korea, Republic of)

    2011-08-26

    Highlights: {yields} Integration of HPV into host genome critical for activation of E6 and E7 oncogenes. {yields} BAF53 is essential for higher-order chromatin structure. {yields} BAF53 knockdown suppresses E6 and E7 from HPV integrants, but not from episomal HPVs. {yields} BAF53 knockdown decreases H3K9Ac and H4K12Ac on P105 promoter of integrated HPV 18. {yields} BAF53 knockdown restores the p53-dependent signaling pathway in HeLa and SiHa cells. -- Abstract: Deregulation of the expression of human papillomavirus (HPV) oncogenes E6 and E7 plays a pivotal role in cervical carcinogenesis because the E6 and E7 proteins neutralize p53 and Rb tumor suppressor pathways, respectively. In approximately 90% of all cervical carcinomas, HPVs are found to be integrated into the host genome. Following integration, the core-enhancer element and P105 promoter that control expression of E6 and E7 adopt a chromatin structure that is different from that of episomal HPV, and this has been proposed to contribute to activation of E6 and E7 expression. However, the molecular basis underlying this chromatin structural change remains unknown. Previously, BAF53 has been shown to be essential for the integrity of higher-order chromatin structure and interchromosomal interactions. Here, we examined whether BAF53 is required for activated expression of E6 and E7 genes. We found that BAF53 knockdown led to suppression of expression of E6 and E7 genes from HPV integrants in cervical carcinoma cell lines HeLa and SiHa. Conversely, expression of transiently transfected HPV18-LCR-Luciferase was not suppressed by BAF53 knockdown. The level of the active histone marks H3K9Ac and H4K12Ac on the P105 promoter of integrated HPV 18 was decreased in BAF53 knockdown cells. BAF53 knockdown restored the p53-dependent signaling pathway in HeLa and SiHa cells. These results suggest that activated expression of the E6 and E7 genes of integrated HPV is dependent on BAF53-dependent higher-order chromatin structure or nuclear motor activity.

  9. Characterization of the transport signals that mediate the nucleocytoplasmic traffic of low risk HPV11 E7

    PubMed Central

    McKee, Courtney H.; Onder, Zeynep; Ashok, Aditya; Cardoso, Rebeca; Moroianu, Junona

    2013-01-01

    We previously discovered that nuclear import of low risk HPV11 E7 is mediated by its zinc-binding domain via a pathway that is independent of karyopherins/importins (Piccioli et al., 2010. Virology 407, 100–109). In this study we mapped and characterized a leucine-rich nuclear export signal (NES), 76IRQLQDLLL84, within the zinc-binding domain that mediates the nuclear export of HPV11 E7 in a CRM1-dependent manner. We also identified a mostly hydrophobic patch 65VRLVV69 within the zinc-binding domain that mediates nuclear import of HPV11 E7 via hydrophobic interactions with the FG-repeats domain of Nup62. Substitutions of hydrophobic residues to alanine within the 65VRLVV69 sequence disrupt the nuclear localization of 11E7, whereas the R66A mutation has no effect. Overall the data support a model of nuclear entry of HPV11 E7 protein via hydrophobic interactions with FG nucleoporins at the nuclear pore complex. PMID:23725695

  10. The nuclear localization of low risk HPV11 E7 protein mediated by its zinc binding domain is independent of nuclear import receptors

    Microsoft Academic Search

    Zachary Piccioli; Courtney H. McKee; Anna Leszczynski; Zeynep Onder; Erin C. Hannah; Shahan Mamoor; Lauren Crosby; Junona Moroianu

    2010-01-01

    We investigated the nuclear import of low risk HPV11 E7 protein using 1) transfection assays in HeLa cells with EGFP fusion plasmids containing 11E7 and its domains and 2) nuclear import assays in digitonin-permeabilized HeLa cells with GST fusion proteins containing 11E7 and its domains. The EGFP-11E7 and EGFP-11cE739–98 localized mostly to the nucleus. The GST-11E7 and GST-11cE739–98 were imported

  11. Cassini Plasma Spectrometer Ion Observations Close to Enceladus: E3, E5 and E7

    NASA Astrophysics Data System (ADS)

    Tokar, R. L.; Johnson, R. E.; Thomsen, M. F.; Wilson, R. J.; Crary, F. J.; Young, D. T.; Goldstein, R.; Reisenfeld, D. B.; Sittler, E. C.; Coates, A. J.; Paty, C. S.; Jia, Y.; Omidi, N.; Russell, C.

    2009-12-01

    The Cassini Plasma Spectrometer (CAPS) detected freshly-produced water-group ions (O+, OH+, H2O+, H3O+) and heavier water dimer ions (HxO2)+ very close to Enceladus where the plasma begins to emerge from the south polar plume (1). The data were obtained during two close (52 and 25 km) flybys of Enceladus in 2008 (E3 and E5) and are consistent with measurements from the Cassini Ion Neutral Mass Spectrometer (INMS). The ions are observed in CAPS detectors looking in the Cassini ram direction close to the ram kinetic energy, indicative of a nearly stagnant plasma flow in the plume. North of Enceladus the plasma slowing commences about 4 to 6 Enceladus radii away, while south of Enceladus signatures of the plasma interaction with the plume are detected 22 Enceladus radii away. Here we review and contrast these observations including the E7 flyby (anticipated Nov. 2, 2009). E7 is planned for a closest approach ~103 km south of Enceladus and CAPS should detect ions at rest with respect to Enceladus and over a broad range of gyrophase angles. Plasma fluid parameters both upstream and downstream of these encounters are extracted from the CAPS data. In addition, we compare the CAPS ion measurements with both fluid and 3D hybrid simulations. The MHD simulations (BATSRUS) are tuned to agree with Cassini Magnetometer (MAG) observations during the encounters then compared with CAPS observations. For example, for the E3 encounter the CAPS/BATSRUS comparison is striking, with features reproduced such as: the overall spatial scale of the interaction, the slowing of the ion flow within the dust plume to less than 5 km/s with respect to Enceladus, the temperature, flow and density signature of the geometric wake, and the flow perturbation along the magnetic field due to wake expansion. For E5, BATSRUS tuned against MAG suggests a 15 km/s bulk plasma flow toward Saturn during the encounter. We search for signatures of this flow in the CAPS ion data. 1.) Tokar,R.L. et al. Geophys. Res. Lett., 36, L13203, doi:10.1029/2009GL038923, 2009.

  12. The PIM family of oncoproteins: Small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets

    PubMed Central

    Shah, Parag P.; Mims, Alice S.; Lockwood, William W.; Kraft, Andrew S.; Beverly, Levi J.

    2014-01-01

    PIM kinases are a family of serine/threonine kinases involved in cell survival and proliferation. There is significant structural similarity between the three PIM kinases (PIM1, PIM2 and PIM3) and few amino acid differences. Although, several studies have specifically monitored the role of PIM1 in tumorigenesis, much less is known about PIM2 and PIM3. Therefore, in this study we have used in vitro cell culture models and in vivo bone marrow infection/transplantation to assess the comparative signaling and oncogenic potential of each of the three PIM kinases. All three PIM kinases were able to protect FL5.12 cells from IL-3 withdrawal induced death. Interestingly, the downstream signaling cascades were indistinguishable between the three kinases. Transplantation of murine bone marrow co-expressing MYC and PIM1, PIM2 or PIM3 caused rapid and uniformly lethal myeloid leukemia. De-induction of MYC 18 days following transplantation significantly increased the survival of mice, even with continual expression of PIM kinases. Alternatively, mice treated at the pre-leukemic stage with a PIM kinase inhibitor increased the lifespan of the mice, even with continual expression of the MYC transgene. These data demonstrate the role of PIM kinases in driving myeloid leukemia, and as candidate molecules for therapy against human malignancies. PMID:25238262

  13. Velocity dispersions in galaxies. I - The E7 galaxy NGC 7332.

    NASA Technical Reports Server (NTRS)

    Morton, D. C.; Chevalier, R. A.

    1972-01-01

    A coude spectrum of the E7 galaxy NGC 7332 with 0.9 A-resolution from 4186 to 4364 A was obtained with the Princeton SEC vidicon television camera and the Hale telescope. Comparisons with spectra of G and K giant stars, numerically broadened for various Maxwellian velocity distributions, give a dispersion velocity in the line of sight of 160 (plus or minus 20) km/sec with the best fit at G8 III. The dispersion appears to be constant within plus or minus 35 km/sec out to 1.4 kpc. After correction for projection, the rotation curve has a slope of 0.18 km/sec per pc at the center and a velocity of 130 km/sec at 1.4 kpc where it is still increasing. For an estimated effective radius of 3.5 kpc enclosing half the light, the virial theorem gives a mass of 140 billion solar masses if the mass-to-light ratio is constant throughout the galaxy.

  14. Immunological and Clinical Responses in Women with Vulval Intraepithelial Neoplasia Vaccinated with a Vaccinia Virus Encoding Human Papillomavirus 16\\/18 Oncoproteins1

    Microsoft Academic Search

    Emma J. Davidson; Christopher M. Boswell; Peter Sehr; Michael Pawlita; Anne E. Tomlinson; Rhona J. McVey; Jennifer Dobson; C. Roberts; Julian Hickling; Henry C. Kitchener; Peter L. Stern

    2003-01-01

    This study assessed the immunological and clinical responses of women with human papillomavirus (HPV) 16-associated high-grade vulval intra- epithelial neoplasia (VIN) vaccinated with TA-HPV, a recombinant vac- cinia virus encoding modified HPV 16 and 18 E6 and E7. Eighteen women with HPV 16-positive high-grade VIN were vaccinated with TA-HPV. The extent of their baseline disease was compared after 24 weeks

  15. A sequence-specific RNase activity derived from the interface of the dimeric immunity protein of the ColE7 operon.

    PubMed

    Liao, Chen-Chung; Chang, Ssu-Jean; Chak, Kin-Fu

    2007-01-01

    Recently, two sequence-specific cleavage sites were found in the ceiE7 gene of the cea-cei-cel polycistronic transcript from the ColE7 operon. The crystal structure of the ColE7 immunity protein (ImE7) suggested that a novel ribonuclease active site is created at the interface of the dimeric structure of the protein. Frame shift mutation of the ceiE7 gene and mutation of histidine residues at the putative active site of the dimeric ImE7 protein respectively abolished and significantly reduced the observed ribonucleolytic cleavage indicating that the dimeric ImE7 protein is indeed involved in this sequence-specific cleavage at the ceiE7 mRNA. It is noteworthy that E. coli S-30 cell extracts must be added to the in vitro reactions in order to detect this ribonucleolytic cleavage. In addition, mutation of the T1 stem-loop structure located between the ceiE7 and the celE7 genes completely turned off the ribonuclease activity in vivo, implying that the T1 stem-loop structure might participate in mediating the formation of a degradosome-like complex required for this specific ribonucleolytic activity. PMID:17305601

  16. Langerhans Cell Homeostasis and Activation Is Altered in Hyperplastic Human Papillomavirus Type 16 E7 Expressing Epidermis

    PubMed Central

    Abd Warif, Nor Malia; Stoitzner, Patrizia; Leggatt, Graham R.; Mattarollo, Stephen R.; Frazer, Ian H.; Hibma, Merilyn H.

    2015-01-01

    It has previously been shown that expression of human papillomavirus type 16 (HPV) E7 in epidermis causes hyperplasia and chronic inflammation, characteristics of pre-malignant lesions. Importantly, E7-expressing epidermis is strongly immune suppressed and is not rejected when transplanted onto immune competent mice. Professional antigen presenting cells are considered essential for initiation of the adaptive immune response that results in graft rejection. Langerhans cells (LC) are the only antigen presenting cells located in normal epidermis and altered phenotype and function of these cells may contribute to the immune suppressive microenvironment. Here, we show that LC are atypically activated as a direct result of E7 expression in the epidermis, and independent of the presence of lymphocytes. The number of LC was significantly increased and the LC are functionally impaired, both in migration and in antigen uptake. However when the LC were extracted from K14E7 skin and matured in vitro they were functionally competent to present and cross-present antigen, and to activate T cells. The ability of the LC to present and cross-present antigen following maturation supports retention of full functional capacity when removed from the hyperplastic skin microenvironment. As such, opportunities are afforded for the development of therapies to restore normal LC function in hyperplastic skin. PMID:25992642

  17. IAC-IIASL B3.8-E7.7 FUTURE DIRECTIONS FOR INTERNATIONAL SPACE COLLABORATION FOR EXPLORATION

    E-print Network

    de Weck, Olivier L.

    1 IAC- IIASL B3.8-E7.7 FUTURE DIRECTIONS FOR INTERNATIONAL SPACE COLLABORATION FOR EXPLORATION Zoe. INTRODUCTION Sustainable space exploration is a challenge that no one nation can do on its own. (Global Exploration Strategy, p.2) Space exploration is an immense undertaking, both technically and financially

  18. Journal of Crystal Growth 275 (2005) e7e13 Numerical study of three-dimensional instabilities in a

    E-print Network

    Gelfgat, Alexander

    2005-01-01

    Journal of Crystal Growth 275 (2005) e7­e13 Numerical study of three-dimensional instabilities the necessary prac- tical answers. In the case of crystal growth, for example, stabilizing the primary of axisym- metric flows in the Czochralski model and simplified flow models related to crystal growth

  19. Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization

    SciTech Connect

    Vandermark, Erik R.; Deluca, Krysta A.; Gardner, Courtney R.; Marker, Daniel F.; Schreiner, Cynthia N.; Strickland, David A.; Wilton, Katelynn M. [Department of Biology, Clarkson University, Potsdam, NY 13699-5805 (United States)] [Department of Biology, Clarkson University, Potsdam, NY 13699-5805 (United States); Mondal, Sumona [Department of Mathematics, Clarkson University, Potsdam, NY 13699-5805 (United States)] [Department of Mathematics, Clarkson University, Potsdam, NY 13699-5805 (United States); Woodworth, Craig D., E-mail: woodworth@clarkson.edu [Department of Biology, Clarkson University, Potsdam, NY 13699-5805 (United States)

    2012-03-30

    The NF-kB family of transcription factors regulates important biological functions including cell growth, survival and the immune response. We found that Human Papillomavirus type 16 (HPV-16) E7 and E6/E7 proteins inhibited basal and TNF-alpha-inducible NF-kB activity in human epithelial cells cultured from the cervical transformation zone, the anatomic region where most cervical cancers develop. In contrast, HPV-16 E6 regulated NF-kB in a cell type- and cell growth-dependent manner. NF-kB influenced immortalization of cervical cells by HPV16. Inhibition of NF-kB by an IkB alpha repressor mutant increased colony formation and immortalization by HPV-16. In contrast, activation of NF-kB by constitutive expression of p65 inhibited proliferation and immortalization. Our results suggest that inhibition of NF-kB by HPV-16 E6/E7 contributes to immortalization of cells from the cervical transformation zone.

  20. Modification of HPV 16 E7 genes: correlation between the level of protein expression and CTL response after immunization of C57BL\\/6 mice

    Microsoft Academic Search

    Thorsten Steinberg; Peter Öhlschläger; Peter Sehr; Wolfram Osen; Lutz Gissmann

    2005-01-01

    Immunization with a codon-optimized HPV 16 E7 gene was shown to yield higher levels of E7-specific cytotoxic T cells [Liu WJ, Gao F, Zhao KN, Zhao W, Fernando GJ, Thomas R, et al. Codon modified human papillomavirus type 16 E7 DNA vaccine enhances cytotoxic T-lymphocyte induction and anti-tumour activity. Virology 2002;301:43]. Here, we sought to verify the hypothesis that there

  1. Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human Papillomavirus Type 11

    Microsoft Academic Search

    Stephen T. Oh; Michelle S. Longworth; Laimonis A. Laimins

    2004-01-01

    Many important functions have been attributed to the high-risk human papillomavirus (HPV) E6 and E7 proteins, including binding and degradation of p53 as well as interacting with Rb proteins. In contrast, the physiological roles of the low-risk E6 and E7 proteins remain unclear. Previous studies demonstrated that the high-risk E6 and E7 proteins also play roles in the productive life

  2. Induction of Antitumor Immunity In vivo Following Delivery of a Novel HPV-16 DNA Vaccine Encoding an E6/E7 Fusion antigen

    PubMed Central

    Yan, Jian; Reichenbach, Dawn K.; Corbitt, Natasha; Hokey, David; Ramanathan, Mathura P.; McKinney, Kibwei A.; Weiner, David B.; Sewell, Duane

    2015-01-01

    Human papillomavirus type 16 (HPV-16) infection is associated with a majority of cervical cancers and a significant proportion of head and neck cancers. Here, we describe a novel engineered DNA vaccine that encodes a HPV-16 consensus E6/E7 fusion gene (pConE6E7) with the goal of increasing its antitumor cellular immunity. Compared to an early stage HPV-16 E7 DNA vaccine (pE7), this construct was up to five times more potent in driving E7-specific cellular immune responses. Prophylactic administration of this vaccine resulted in 100% protection against HPV E6 and E7-expressing tumors. Therapeutic studies indicated that vaccination with pConE6E7 prevented or delayed the growth of tumors. Moreover, immunization with pConE6E7 could also partially overcome immune tolerance in E6/E7 transgenic mice. Such DNA immunogens are interesting candidates for further study to investigate mechanisms of tumor immune rejection in vivo. PMID:19022315

  3. The Nuclear Localization of Low Risk HPV11 E7 Protein Mediated by its Zinc Binding Domain Is Independent of Nuclear Import Receptors

    PubMed Central

    Piccioli, Zachary; McKee, Courtney H.; Leszczynski, Anna; Onder, Zeynep; Hannah, Erin C.; Mamoor, Shahan; Crosby, Lauren; Moroianu, Junona

    2010-01-01

    We investigated the nuclear import of low risk HPV11 E7 protein using 1) transfection assays in HeLa cells with EGFP fusion plasmids containing 11E7 and its domains and 2) nuclear import assays in digitonin-permeabilized HeLa cells with GST fusion proteins containing 11E7 and its domains. The EGFP-11E7 and EGFP-11cE739–98 localized mostly to the nucleus. The GST-11E7 and GST-11cE739–98 were imported into the nuclei in the presence of either Ran-GDP or RanG19V-GTP mutant and in the absence of nuclear import receptors. This suggests that 11E7 enters the nucleus via a Ran-dependent pathway, independent of nuclear import receptors, mediated by a nuclear localization signal located in its C-terminal domain (cNLS). This cNLS contains the zinc-binding domain consisting of two copies of Cys-X-X-Cys motif. Mutagenesis of Cys residues in these motifs changed the localization of the EGFP-11cE7/-11E7 mutants to cytoplasmic, suggesting that the zinc-binding domain is essential for nuclear localization of 11E7. PMID:20800258

  4. !"#$%&'() *+$%+( ,-.(/(0#(1 2-,-%+ 3%$(4 5+$%+( 6%#1714 89%$(4*+$%+($%#1714:/*0;: .5/+0:,?2@ A*"B$() '71)C&*DE E%&&"( &%0"$7E%*+ 9%E' /*+E7/E 7+) /*+&E17%+E&

    E-print Network

    Paris-Sud XI, Université de

    >/+0:,?2@ A*"B$() '71)C&*DE E%&&"( &%0"$7E%*+ 9%E' /*+E7/E 7+) /*+&E17%+E& 7BB$%() E* F79CE*+G"(C'4*%) )4%."%, BNOCD I$ F%)(-8", M%$(-" HPQQRSN 3( B1(&(+E 7+ *B(+T&*"1/( B'4&%/7$ &%0"$7E%*+ &4&E(0 &"%E7#$( D*1 (D E 0*)($%+G *D 7+7E*0%/7$ &E1"/E"1(& /*0B*&() *D #*E' '71) 7+) &*DE E%&&"( /*0B*+(+E&K %+E(1/*++(/E

  5. Chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine generates different anti-tumor effects against tumors expressing the E7 protein of human papillomavirus.

    PubMed

    Khavari, Afshin; Bolhassani, Azam; Alizadeh, Fatemeh; Bathaie, S Zahra; Balaram, Prabha; Agi, Elnaz; Vahabpour, Rouhollah

    2015-02-01

    Saffron and its components have been suggested as promising candidates for cancer prevention. Carotenoids and monoterpene aldehydes are two potent ingredients of saffron. The goal of the current study was to investigate the anti-tumor effect of chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine against tumors expressing the E7 protein of human papillomavirus. The in vitro cytotoxic and apoptotic effects of aqueous saffron extract and its components were evaluated in malignant TC-1 and non-malignant COS-7 cell lines. Then, multimodality treatments using E7-NT (gp96) DNA vaccine combined with saffron extract and its ingredients as well as single-modality treatments were tested for their efficacy in inhibiting large and bulky tumor growth. Saffron and its components exerted a considerable anti-tumor effect through prevention of cell growth and stimulation of programmed cell death. Furthermore, 100 % of mice treated with crocin were tumor-free, in contrast to DNA vaccine alone (~66.7 %) and DNA + crocin (~33.3 %) indicating the high potency of crocin as a chemotherapeutic agent. Interestingly, the multimodality treatment using DNA vaccine along with picrocrocin augmented the anti-tumor effects of picrocrocin. Thus, the combination of DNA vaccine with saffron extract and crocin at certain concentrations did not potentiate protective and therapeutic effects compared to mono-therapies for the control of TC-1 tumors. PMID:25395243

  6. Oncoprotein protein kinase antibody kit

    DOEpatents

    Karin, Michael (San Diego, CA); Hibi, Masahiko (San Diego, CA); Lin, Anning (La Jolla, CA)

    2008-12-23

    An isolated polypeptide (JNK) characterized by having a molecular weight of 46 kD as determined by reducing SDS-PAGE, having serine and threonine kinase activity, phosphorylating the c-Jun N-terminal activation domain and polynucleotide sequences and method of detection of JNK are provided herein. JNK phosphorylates c-Jun N-terminal activation domain which affects gene expression from AP-1 sites.

  7. Rational R-matrices, centralizer algebras and tensor identities for e6 and e7 exceptional families of Lie algebras

    NASA Astrophysics Data System (ADS)

    MacKay, N. J.; Taylor, A.

    2007-10-01

    We use Cvitanovi?'s [Group Theory (Princeton University Press, Princeton, NJ, in press) (http://www.nbi.dk/GroupTheory/); Phys. Rev. D 14, 1536 (1976)] diagrammatic techniques to construct the rational solutions of the Yang-Baxter equation [Yang-Baxter Equation in Integrable Systems, edited by M. Jimbo, Advanced Series in Mathematical Physics Vol. 10 (World scientific, Singapore, 1990)] associated with the e6 and e7 families of Lie algebras, and thus explain Westbury's [J. Phys. A 36, 2857 (2003)] observations about their uniform spectral decompositions. In doing so, we explore the extensions of the Brauer and symmetric group algebras to the centralizer algebras of e7 and e6 on their lowest-dimensional representations and (up to threefold) tensor products thereof, giving bases for them and a range of identities satisfied by the algebras' defining invariant tensors.

  8. Efficiency of HPV 16 L1\\/E7 DNA immunization: Influence of cellular localization and capsid assembly

    Microsoft Academic Search

    Dirk Kuck; Christoph Leder; Andrea Kern; Martin Müller; Konrad Piuko; Lutz Gissmann; Jürgen A. Kleinschmidt

    2006-01-01

    Infections by human papillomaviruses (HPV) are the major cause of uterine cancer in women worldwide. Aiming to develop a combined prophylactic and therapeutic vaccine we have previously demonstrated immunogenicity of chimeric virus-like particles consisting of a C-terminally truncated HPV 16 L1 capsid protein fused to an E7 portion. Here we show that genetic vaccination with a corresponding DNA was inefficient

  9. A Note on Single Soft Scalar Emission of $\\mathcal{N}=8$ SUGRA and $E_{7(7)}$ Symmetry

    E-print Network

    Song He; Huaxing Zhu

    2010-08-09

    We study single soft scalar emission amplitudes of $\\mathcal{N}=8$ supergravity (SUGRA) at the one-loop level using an explicit formula for one-loop amplitudes in terms of tree amplitudes, which in turn are evaluated using supersymmetric BCFW recursion relations. It turns out that the infrared finite parts of all such amplitudes vanish in the soft momentum limit, which supports the conjecture that $E_{7(7)}$ symmetry has no anomalies at the one-loop level.

  10. Safety and Efficacy of Adalimumab (D2E7) in Crohn's Disease Patients with an Attenuated Response to Infliximab

    Microsoft Academic Search

    Konstantinos A. Papadakis; Omid A. Shaye; Eric A. Vasiliauskas; Andrew Ippoliti; Marla C. Dubinsky; Jaime Birt; Jane Paavola; Susie K. Lee; Joanne Price; Stephan R. Targan; Maria T. Abreu

    2005-01-01

    OBJECTIVES:Although infliximab is highly effective in the treatment of Crohn's disease (CD), attenuated response to infliximab may develop over time in a subgroup of patients. The aim of our study was to examine the safety and efficacy of adalimumab (D2E7), a fully humanized anti-TNF-? Ab, in CD patients who had experienced an attenuated response to infliximab.METHODS:Fifteen patients with active CD

  11. Induction of focal epithelial hyperplasia in tongue of young bk6-E6/E7 HPV16 transgenic mice.

    PubMed

    Ocadiz-Delgado, Rodolfo; Marroquin-Chavira, Alberto; Hernandez-Mote, Ruth; Valencia, Concepción; Manjarrez-Zavala, M Eugenia; Covarrubias, Luis; Gariglio, Patricio

    2009-08-01

    Squamous cell carcinoma (SCC) of the oral cavity is one of the most common neoplasms in the world. During the past 2 decades, the role of high-risk human papilloma virus (HR-HPV) has been studied and the data supporting HPV as a one of the causative agents in the development and progression of a sub-set of head and neck squamous cell carcinomas (HNSCC) has accumulated. In order to investigate the role of HR-HPV oncogene expression in early epithelial alterations in vivo, we produced transgenic mice expressing HPV16 early region genes from the promoter of the bovine keratin 6 gene (Tg[bK6-E6/E7]). In this article, we demonstrate that E6/E7 transgene was abundantly expressed and cellular proliferation was increased in the middle tongue epithelia of transgenic mice, and that in the same region young (27 weeks old) Tg[bK6-E6/E7] mice spontaneously developed histological alterations, mainly focal epithelial hyperplasia (FEH). PMID:19165615

  12. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation.

    PubMed

    Magaldi, Thomas G; Almstead, Laura L; Bellone, Stefania; Prevatt, Edward G; Santin, Alessandro D; DiMaio, Daniel

    2012-01-01

    Repression of human papillomavirus (HPV) E6 and E7 oncogenes in established cervical carcinoma cell lines causes senescence due to reactivation of cellular tumor suppressor pathways. Here, we determined whether ongoing expression of HPV16 or HPV18 oncogenes is required for the proliferation of primary human cervical carcinoma cells in serum-free conditions at low passage number after isolation from patients. We used an SV40 viral vector expressing the bovine papillomavirus E2 protein to repress E6 and E7 in these cells. To enable efficient SV40 infection and E2 gene delivery, we first incubated the primary cervical cancer cells with the ganglioside GM1, a cell-surface receptor for SV40 that is limiting in these cells. Repression of HPV in primary cervical carcinoma cells caused them to undergo senescence, but the E2 protein had little effect on HPV-negative primary cells. These data suggest that E6 and E7 dependence is an inherent property of human cervical cancer cells. PMID:22056390

  13. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation

    SciTech Connect

    Magaldi, Thomas G.; Almstead, Laura L. [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States)] [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States); Bellone, Stefania [Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, P.O. Box 208063, New Haven, CT 06520-8063 (United States)] [Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, P.O. Box 208063, New Haven, CT 06520-8063 (United States); Prevatt, Edward G. [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States)] [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States); Santin, Alessandro D. [Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, P.O. Box 208063, New Haven, CT 06520-8063 (United States) [Department of Obstetrics and Gynecology and Reproductive Sciences, Yale School of Medicine, P.O. Box 208063, New Haven, CT 06520-8063 (United States); Yale Comprehensive Cancer Center, P.O. Box 208028, New Haven, CT 06520-8028 (United States); DiMaio, Daniel, E-mail: daniel.dimaio@yale.edu [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States) [Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005 (United States); Department of Therapeutic Radiology, Yale School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040 (United States); Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, P.O. Box 208024 (United States); Yale Comprehensive Cancer Center, P.O. Box 208028, New Haven, CT 06520-8028 (United States)

    2012-01-05

    Repression of human papillomavirus (HPV) E6 and E7 oncogenes in established cervical carcinoma cell lines causes senescence due to reactivation of cellular tumor suppressor pathways. Here, we determined whether ongoing expression of HPV16 or HPV18 oncogenes is required for the proliferation of primary human cervical carcinoma cells in serum-free conditions at low passage number after isolation from patients. We used an SV40 viral vector expressing the bovine papillomavirus E2 protein to repress E6 and E7 in these cells. To enable efficient SV40 infection and E2 gene delivery, we first incubated the primary cervical cancer cells with the ganglioside GM1, a cell-surface receptor for SV40 that is limiting in these cells. Repression of HPV in primary cervical carcinoma cells caused them to undergo senescence, but the E2 protein had little effect on HPV-negative primary cells. These data suggest that E6 and E7 dependence is an inherent property of human cervical cancer cells.

  14. Human papillomavirus type 18 E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization, and transformation but not for Rb binding.

    PubMed

    McIntyre, M C; Frattini, M G; Grossman, S R; Laimins, L A

    1993-06-01

    Human papillomavirus type 18 (HPV-18) E7 proteins bind zinc through Cys-X-X-Cys repeats located at the C terminus of the protein. In order to examine the role of these cysteine motifs in E7 function, we expressed the HPV-18 E7 protein in bacteria and found that purified E7 forms a dimer through interactions with zinc. Mutants with single mutations within the Cys-X-X-Cys motifs bound a reduced level of zinc in a zinc blot assay, while a double mutant lost all zinc-binding activity. When expressed in vivo, none of the mutants cooperated with an activated ras oncogene to transform primary rat embryo fibroblasts, but all mutants retained nearly wild-type Rb-binding activity. The results indicate that the cysteine motifs play an important role in transformation by HPV-18 E7 but do not contribute to Rb binding. PMID:8497045

  15. Human papillomavirus type 18 E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization, and transformation but not for Rb binding.

    PubMed Central

    McIntyre, M C; Frattini, M G; Grossman, S R; Laimins, L A

    1993-01-01

    Human papillomavirus type 18 (HPV-18) E7 proteins bind zinc through Cys-X-X-Cys repeats located at the C terminus of the protein. In order to examine the role of these cysteine motifs in E7 function, we expressed the HPV-18 E7 protein in bacteria and found that purified E7 forms a dimer through interactions with zinc. Mutants with single mutations within the Cys-X-X-Cys motifs bound a reduced level of zinc in a zinc blot assay, while a double mutant lost all zinc-binding activity. When expressed in vivo, none of the mutants cooperated with an activated ras oncogene to transform primary rat embryo fibroblasts, but all mutants retained nearly wild-type Rb-binding activity. The results indicate that the cysteine motifs play an important role in transformation by HPV-18 E7 but do not contribute to Rb binding. Images PMID:8497045

  16. [Construction and eukaryotic expression of PVAX1-hPV58mE6E7fcGB composite gene vaccine].

    PubMed

    Wang, He; Yu, Jiyun; Li, Li

    2013-10-01

    To construct and express a composite gene vaccine for human papillomavirus 58(HPV58)-associated cervical cancer, we inserted HPV58mE6E7 fusion gene into pCI-Fc-GPI eukaryotic expression vector, constructing a recombinant plasmid named pCI-sig-HPV58mE6E7-Fc-GPI. Then we further inserted fragment of sig-HPV58mE6E7Fc-GPI into the novel vaccine vector PVAX1-IRES-GM/B7, constructing PVAX1-HPV58mE6E7FcGB composite gene vaccine. PVAX1-HPV58mE6E7FcGB vaccine was successfully constructed and identified by restriction endonuclease and sequencing analysis. Eukaryotic expression of fusion antigen sig-HPV58mE6E7-Fc-GPI and molecular ad-juvant GM-CSF and B7. 1 were proved to be realized at the same time by flow cytometry and immunofluorescence. So PVAX1-HPV58mE6E7FcGB can be taken as a candidate of therapeutic vaccine for HPV58-associated tumors and their precancerous transformations. PMID:24459978

  17. Translational fusion and redirection to thylakoid lumen as strategies to enhance accumulation of human papillomavirus E7 antigen in tobacco chloroplasts.

    PubMed

    Morgenfeld, Mauro; Lentz, Ezequiel; Segretin, María Eugenia; Alfano, E Federico; Bravo-Almonacid, Fernando

    2014-11-01

    Human papillomavirus (HPV) is the causal agent of cervical cancer, one of the most common causes of death in women worldwide, and its E7 antigen is the major candidate for a therapeutic vaccine. The large scale production of E7 by molecular farming that would lead to the development of a safe and inexpensive vaccine is impaired by its low accumulation level in the plant cell. To enhance antigen production in the plastids, two alternative strategies were carried out: the expression of E7 as a translational fusion to ?-glucuronidase enzyme and redirection of E7 into the thylakoid lumen. The use of the ?-glucuronidase as a partner protein turned out to be a successful strategy, antigen expression levels were enhanced between 30 and 40 times relative to unfused E7. Moreover, best accumulation, albeit at a high metabolic cost that compromised biomass production, was obtained redirecting E7 into the thylakoid lumen by the incorporation of the N-terminal transit peptide, Str. Following this approach lumenal E7 production exceeded the stromal by two orders of magnitude. Our results highlight the relevance of exploring different strategies to improve recombinant protein stability for certain transgenes in order to exploit potential advantages of recombinant protein accumulation in chloroplasts. PMID:24981330

  18. M E D I C I N E TUF TS V O L U M E 7 , N O . 3

    E-print Network

    Tufts University

    SCHOOL OF VETERINARY MEDICINE veterinary m e d i c i n e TUF TS P L U S : A N E W M O D E L F O R C O E X illustrates the intersection of mul- tiple aspects of veterinary medicine, in particular, domestic poultryVETERINARY M E D I C I N E TUF TS V O L U M E 7 , N O . 3 S P R I N G 2 0 0 6 MAGAZINE OF CUMMINGS

  19. Development of a Multiplex PCR Test with Automated Genotyping Targeting E7 for Detection of Six High-Risk Human Papillomaviruses

    PubMed Central

    de Assis, Angela Maria

    2015-01-01

    Cervical cancer is caused by high-risk human papillomaviruses (HPV) and viral detection tests aid in the diagnosis of precursor lesions. In the present study, a molecular test for detection of high-risk HPV DNA, called E7-HPV, was standardized and assessed in samples from women with pre-cancerous lesions. The development of the E7-HPV test for detection and genotyping of six high-risk HPV (types 16, 18, 31, 33, 45 and 52), consisted of evaluating primer quality and adjusting the multiplex PCR conditions. Primer design was based on the E7 region of each HPV, and the fluorochrome 6-FAM was added to PCR primers. Viral detection was performed by capillary electrophoresis in automated sequencer in samples obtained from 60 women (55 with ASC-H/HSIL cytology) from August to September 2013. A non-inferiority analysis was conducted with the cobas HPV test as a reference and following international guidelines for the development of new tests. The two tests had a high concordance rate in HPV16 detection (kappa=0.972), with only one discordant case (cervical intraepithelial neoplasia grade 3, negaive with cobas and positive for HPV16 by E7-HPV) and complete agreement in HPV18 detection. When comparing detection of all high-risk HPV, three cases were positive with cobas but negative with E7-HPV, and another three cases were negative with cobas but positive with E7-HPV (HPV16, 31 and 52). When we evaluate the cases initially suspected by cytology, the two tests had the same sensitivity in detection CIN2 or worse. In conclusion, the E7-HPV test has satisfactory initial results, and its development can be continued. PMID:26087285

  20. Artificial Transmembrane Oncoproteins Smaller than the Bovine Papillomavirus E5 Protein Redefine Sequence Requirements for Activation of the Platelet-Derived Growth Factor   Receptor

    Microsoft Academic Search

    Kristina Talbert-Slagle; Sara Marlatt; Francisco N. Barrera; Ekta Khurana; Joanne Oates; Mark Gerstein; Donald M. Engelman; Ann M. Dixon; Daniel DiMaio

    2009-01-01

    The bovine papillomavirus E5 protein (BPV E5) is a 44-amino-acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the platelet-derived growth factor (PDGF) receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane

  1. A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting.

    PubMed

    Martorelli, Debora; Muraro, Elena; Mastorci, Katy; Dal Col, Jessica; Faè, Damiana Antonia; Furlan, Chiara; Giagulli, Cinzia; Caccuri, Francesca; Rusnati, Marco; Fiorentini, Simona; Carbone, Antonino; Caruso, Arnaldo; Dolcetti, Riccardo

    2015-09-01

    Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV(+) B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting. PMID:25704763

  2. Induction of stable p53 oncoprotein and of c-myc overexpression in cultured normal human uroepithelium by radiation and N-nitrosodiethanolamine

    SciTech Connect

    Mothersill, C.; Seymour, C.B. (Dublin Institute of Technology, Dublin (Ireland)); Harney, J. (Beaumont Hospital, Dublin (Ireland))

    1994-04-01

    Uroepithelium cultured from normal patients without cancer (60 individuals) was found to segregate into four subtypes based on the level of carcinogen treatment needed to induce abnormal p53 and c-myc. Twenty-two percent of patient cultures never showed abnormal p53 expression, even after chronic exposure to nitrosamines, while a further 26% required only a single dose of radiation to induce the abnormal protein. The remaining patients had tissues which, while initially negative for stable p53, became positive when put into culture and stimulated to grow. The c-myc protein was overexpressed in all cultures with abnormal p53. It would appear that elevated expression of conformationally inactive p53 and of high levels of c-myc represents an early response of normal uroepithelial cells to carcinogen challenge. It also appears that a relatively high number of patients without cancer express these proteins when their cells are challenged to grow; a pre-exposure to environmental carcinogens such as nitrosamines in cigarette smoke is likely to be involved. 30 refs., 3 figs., 3 tabs.

  3. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.

    PubMed

    Xiang, Di; Yuan, Yunsheng; Chen, Li; Liu, Xin; Belani, Chandra; Cheng, Hua

    2015-08-14

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and I?B kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells. PMID:26116531

  4. Molecular orientational and dipolar correlation in the liquid crystal mixture E7: a molecular dynamics simulation study at a fully atomistic

    E-print Network

    Wilson, Mark R.

    .1039/b614422e Molecular dynamics simulations are reported for the four component nematic liquid crystal, dielectric anisotropy and elastic constants, properties that critically influence the performance of a liquidMolecular orientational and dipolar correlation in the liquid crystal mixture E7: a molecular

  5. Honeybee venom possesses anticancer and antiviral effects by differential inhibition of HPV E6 and E7 expression on cervical cancer cell line.

    PubMed

    Kim, Yong-Wan; Chaturvedi, Pankaj Kumar; Chun, Sung Nam; Lee, Yang Gu; Ahn, Woong Shick

    2015-04-01

    Bee venom (BV) therapy is a type of alternative medical treatment used to treat various diseases in oriental medicine. The mechanisms underlying the effects of BV remain poorly understood. In the present study, we evaluated the antiviral effect of BV on cervical carcinoma cell lines (CaSki, HeLa, C33A and TC-1). BV treatments resulted in a more significant suppression of cell growth in HPV 16-infected cells (CaSki) and a lesser suppression in HPV 18-infected cells (HeLa). However, less suppression was observed in HPV-negative C33A cells. In 10 µg/ml BV-treated CaSki cells, the mRNA expression and protein levels of HPV16 E6 and E7 were significantly decreased by BV, while HPV18 E6 and E7 mRNA expression levels were not significantly altered by 10 µg/ml BV-treated HeLa cells. The antitumor effects of BV were in accordance with in vitro data, in restricting tumor growth in vivo and were much more effective on the suppression of tumor growth. Furthermore, the mRNA and protein expression levels of HPV16 E6 and E7 were decreased by BV in TC-1 tumors. These findings demonstrated the antiviral effects of BV in HPV-infected cervical cancer cells and the anticancer effects of BV in HPV16 E6/E7-expressed TC-1 tumors. Collectively, BV plays a differential role in suppressing HPV16-infected cells (CaSki cells) and HPV18-infected cells (HeLa cells) by the downregulation of E6/E7 protein of HPV16/18. PMID:25633640

  6. HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women.

    PubMed

    Duvlis, Sotirija; Popovska-Jankovic, Katerina; Arsova, Zorica Sarafinovska; Memeti, Shaban; Popeska, Zaneta; Plaseska-Karanfilska, Dijana

    2015-09-01

    High risk types of human papillomaviruses E6/E7 oncogenes and their association with tumor suppressor genes products are the key factors of cervical carcinogenesis. This study proposed them as specific markers for cervical dysplasia screening. The aim of the study is to compare the clinical and prognostic significance of HPV E6/E7 mRNA as an early biomarker versus HPV DNA detection and cytology in triage of woman for cervical cancer. The study group consists of 413 women: 258 NILM, 26 ASC-US, 81 LSIL, 41 HSIL, and 7 unsatisfactory cytology. HPV4AACE screening, real-time multiplex PCR and MY09/11 consensus PCR primers methods were used for the HPV DNA detection. The real-time multiplex nucleic acid sequence-based assay (NucliSENS EasyQ HPV assay) was used for HPV E6/E7 mRNA detection of the five most common high risk HPV types in cervical cancer (16, 18, 31, 33, and 45). The results show that HPV E6/E7 mRNA testing had a higher specificity 50% (95% CI 32-67) and positive predictive value (PPV) 62% (95% CI 46-76) for CIN2+ compared to HPV DNA testing that had specificity of 18% (95% CI 7-37) and PPV 52% (95% CI 39-76) respectively. The higher specificity and PPV of HPV E6/E7 mRNA testing are valuable in predicting insignificant HPV DNA infection among cases with borderline cytological finding. It can help in avoiding aggressive procedures (biopsies and over-referral of transient HPV infections) as well as lowering patient's anxiety and follow up period. J. Med. Virol. 87:1578-1586, 2015. © 2015 Wiley Periodicals, Inc. PMID:25880030

  7. Oncogenicity of human papillomavirus- or adenovirus-transformed cells correlates with resistance to lysis by natural killer cells.

    PubMed Central

    Routes, J M; Ryan, S

    1995-01-01

    The reasons for the dissimilar oncogenicities of human adenoviruses and human papillomaviruses (HPV) in humans are unknown but may relate to differences in the capacities of the E1A and E7 proteins to target cells for rejection by the host natural killer (NK) cell response. As one test of this hypothesis, we compared the abilities of E1A- and E7-expressing human fibroblastic or keratinocyte-derived human cells to be selectively killed by either unstimulated or interferon (IFN)-activated NK cells. Cells expressing the E1A oncoprotein were selectively killed by unstimulated NK cells, while the same parental cells but expressing the HPV type 16 (HPV-16) or HPV-18 E7 oncoprotein were resistant to NK cell lysis. The ability of IFN-activated NK cells to selectively kill virally transformed cells depends on IFN's ability to induce resistance to NK cell lysis in normal (i.e., non-viral oncogene-expressing) but not virally transformed cells. E1A blocked IFN's induction of cytolytic resistance, resulting in the selective lysis of adenovirus-transformed cells by IFN-activated NK cells. The extent of IFN-induced NK cell killing of E1A-expressing cells was proportional to the level of E1A expression and correlated with the ability of E1A to block IFN-stimulated gene expression in target cells. In contrast, E7 blocked neither IFN-stimulated gene expression nor IFN's induction of cytolytic resistance, thereby precluding the selective lysis of HPV-transformed cells by IFN-activated NK cells. In conclusion, E1A expression marks cells for destruction by the host NK cell response, whereas the E7 oncoprotein lacks this activity. PMID:7494272

  8. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias.

    PubMed Central

    McWhirter, J R; Wang, J Y

    1993-01-01

    In Philadelphia chromosome-positive human leukemias, which include chronic myelogenous leukemia and some acute lymphocytic leukemias, the c-abl proto-oncogene on chromosome 9 becomes fused to the bcr gene on chromosome 22, and Bcr-Abl fusion proteins are produced. The Bcr sequences activate the Abl tyrosine kinase which is required for the transforming function of Bcr-Abl. The Bcr sequences also enhance an F-actin-binding activity associated with c-Abl. Here, we show that binding of c-Abl and Bcr-Abl proteins to actin filaments in vivo and in vitro is mediated by an evolutionarily conserved domain at the C-terminal end of c-Abl. The c-Abl F-actin-binding domain contains a consensus motif found in several other actin-crosslinking proteins. Mutations in the consensus motif are shown to abolish binding to F-actin. Bcr-Abl proteins unable to associate with F-actin have a reduced ability to transform Rat-1 fibroblasts and to abrogate the requirement for interleukin-3 in the lymphoblastoid cell line Ba/F3. In transformed cells, Bcr-Abl induces a redistribution of F-actin into punctate, juxtanuclear aggregates. The binding to actin filaments has important implications for the pathogenic and physiological functions of the Bcr-Abl and c-Abl proteins. Images PMID:8467803

  9. Acetylation of the human T-cell leukemia virus type 1 Tax oncoprotein by p300 promotes activation of the NF-?B pathway

    PubMed Central

    Lodewick, Julie; Lamsoul, Isabelle; Polania, Angela; Lebrun, Sylvie; Burny, Arsène; Ratner, Lee; Bex, Françoise

    2010-01-01

    The oncogenic potential of the HTLV-1 Tax protein involves activation of the NF-?B pathway, which depends on Tax phosphorylation, ubiquitination and sumoylation. We demonstrate that the nuclei of Tax-expressing cells, including HTLV-1 transformed T-lymphocytes, contain a pool of Tax molecules acetylated on lysine residue at amino acid position 346 by the transcriptional coactivator p300. Phosphorylation of Tax on serine residues 300/301 was a prerequisite for Tax localization in the nucleus and correlated with its subsequent acetylation by p300, whereas sumoylation, resulting in the formation of Tax nuclear bodies in which p300 was recruited, favored Tax acetylation. Overexpression of p300 markedly increased Tax acetylation and the ability of a wild type HTLV-1 provirus, –but not of a mutant provirus carrying an acetylation deficient Tax gene–, to activate gene expression from an integrated NF-?B-controlled promoter. Thus, Tax acetylation favors NF-?B activation and might play an important role in HTLV-1-induced cell transformation. PMID:19200568

  10. Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding to and repression of an erythroid enhancer in vivo.

    PubMed Central

    Ciana, P; Braliou, G G; Demay, F G; von Lindern, M; Barettino, D; Beug, H; Stunnenberg, H G

    1998-01-01

    v-ErbA, a mutated thyroid hormone receptor alpha (TRalpha), is thought to contribute to avian erythroblastosis virus (AEV)-induced leukemic transformation by constitutively repressing transcription of target genes. However, the binding of v-ErbA or any unliganded nuclear receptor to a chromatin-embedded response element as well as the role of the N-CoR-SMRT-HDAC co-repressor complex in mediating repression remain hypothetical. Here we identify a v-ErbA-response element, VRE, in an intronic DNase I hypersensitive site (HS2) of the chicken erythroid carbonic anhydrase II (CAII) gene. In vivo footprinting shows that v-ErbA is constitutively bound to this HS2-VRE in transformed, undifferentiated erythroblasts along with other transcription factors like GATA-1. Transfection assays show that the repressed HS2 region can be turned into a potent enhancer in v-ErbA-expressing cells by mutation of the VRE. Differentiation of transformed cells alleviates v-ErbA binding concomitant with activation of CAII transcription. Co-expression of a gag-TRalpha fusion protein in AEV-transformed cells and addition of ligand derepresses CAII transcription. Treatment of transformed cells with the histone deacetylase inhibitor, trichostatin A, derepresses the endogenous, chromatin-embedded CAII gene, while a transfected HS2-enhancer construct remains repressed. Taken together, our data suggest that v-ErbA prevents CAII activation by 'neutralizing' in cis the activity of erythroid transcription factors. PMID:9857194

  11. CRM1-mediated nuclear export is required for 26 S proteasome-dependent degradation of the TRIP-Br2 proto-oncoprotein.

    PubMed

    Cheong, Jit Kong; Gunaratnam, Lakshman; Hsu, Stephen I-Hong

    2008-04-25

    Overexpression of the proto-oncogene TRIP-Br2 (SERTAD2) has been shown to induce E2F activity and promote tumorigenesis, whereas ablation of TRIP-Br2 arrests cell proliferation. Timely degradation of many cell cycle regulators is fundamental to the maintenance of proper cell cycle progression. Here we report novel mechanism(s) that govern the tight regulation of TRIP-Br2 levels during cell cycle progression. TRIP-Br2 was observed to be a short-lived protein in which the expression level peaks at the G(1)/S boundary. TRIP-Br2 accumulated in cells treated with 26 S proteasome inhibitors. Co-immunoprecipitation studies revealed that TRIP-Br2 forms ubiquitin conjugates. In silico analysis identified a putative leucine-rich nuclear export signal (NES) motif that overlaps with the PHD-Bromo interaction domain in the acidic C-terminal transactivation domain (TAD) of TRIP-Br2. This NES motif is highly conserved in widely divergent species and in all TRIP-Br family members. TRIP-Br2 was shown to be stabilized in G(2)/M phase cells through nuclear entrapment, either by deletion of the acidic C-terminal TAD, which includes the NES motif, or by leptomycin B-mediated inhibition of the CRM1-dependent nuclear export machinery. Mutation of leucine residue 238 of this NES motif abolished the interaction between CRM1 and TRIP-Br2, as well as the nuclear export of TRIP-Br2 and its subsequent 26 S proteasome-dependent degradation. These data suggest that CRM1-mediated nuclear export may be required for the proper execution of ubiquitin-proteasome-dependent degradation of TRIP-Br2. PMID:18316374

  12. Protective anti-tumor immunity induced by vaccination with recombinant adenoviruses encoding multiple tumor-associated cytotoxic T lymphocyte epitopes in a string-of-beads fashion.

    PubMed

    Toes, R E; Hoeben, R C; van der Voort, E I; Ressing, M E; van der Eb, A J; Melief, C J; Offringa, R

    1997-12-23

    Vaccines harboring genes that encode functional oncoproteins are intrinsically hazardous, as their application may lead to introduction of these genes into normal cells and thereby to tumorigenesis. On the other hand, oncoproteins are especially attractive targets for immunotherapy of cancer, as their expression is generally required for tumor growth, making the arisal of tumor variants lacking these antigens unlikely. Using murine tumor models, we investigated the efficacy of polyepitope recombinant adenovirus (rAd) vaccines, which encode only the immunogenic T cell epitopes derived from several oncogenes, for the induction of protective anti-tumor immunity. We chose to employ rAd, as these are safe vectors that do not induce the side effects associated with, for example, vaccinia virus vaccines. A single polyepitope rAd was shown to give rise to presentation of both H-2 and human leukocyte antigen-restricted cytotoxic T lymphocyte (CTL) epitopes. Moreover, vaccination with a rAd encoding H-2-restricted CTL epitopes, derived from human adenovirus type 5 early region 1 and human papilloma virus type 16-induced tumors, elicited strong tumor-reactive CTL and protected the vaccinated animals against an otherwise lethal challenge with either of these tumors. The protection induced was superior compared with that obtained by vaccination with irradiated tumor cells. Thus, vaccination with polyepitope rAd is a powerful approach for the induction of protective anti-tumor immunity that allows simultaneous immunization against multiple tumor-associated T cell epitopes, restricted by various major histocompatibility complex haplotypes. PMID:9405669

  13. The Human DEK ProtoOncogene Is a Senescence Inhibitor and an Upregulated Target of High-Risk Human Papillomavirus E7

    Microsoft Academic Search

    Trisha M. Wise-Draper; Hillary V. Allen; Megan N. Thobe; Elizabeth E. Jones; Kristen B. Habash; Karl Munger; Susanne I. Wells

    2005-01-01

    The human DEK proto-oncogene is a nucleic acid binding protein with suspected roles in human carcino- genesis, autoimmune disease, and viral infection. Intracellular DEK functions, however, are poorly understood. In papillomavirus-positive cervical cancer cells, downregulation of viral E6\\/E7 oncogene expression results in cellular senescence. We report here the specific repression of DEK message and protein levels in senescing human papillomavirus

  14. Inhibition of cervical cancer cell growth in vitro and in vivo with lentiviral-vector delivered short hairpin RNA targeting human papillomavirus E6 and E7 oncogenes

    Microsoft Academic Search

    W Gu; L Putral; K Hengst; K Minto; N A Saunders; G Leggatt; N A J McMillan

    2006-01-01

    In this study, we investigated the suppressive effect of a short hairpin RNA delivered by a lentiviral vector (LV-shRNA) against human papillomavirus (HPV) type 18 E6 on the expression of the oncogenes E6 and E7 in cervical cancer HeLa cells both in vitro and in vivo. The LV-shRNA effectively delivered the shRNA to HeLa cells and lead to a dose-dependent

  15. Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity

    Microsoft Academic Search

    Balasubramanyam Karanam; Ratish Gambhira; Shiwen Peng; Subhashini Jagu; Dae-Jin Kim; Gary W. Ketner; Peter L. Stern; Robert J. Adams; Richard B. S. Roden

    2009-01-01

    A vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN

  16. A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

    Microsoft Academic Search

    Xuelian Wang; Alessandro D. Santin; Stefania Bellone; Sushil Gupta; Mayumi Nakagawa

    2009-01-01

    Previously, safety and immunogenicity of human papillomavirus type 16 (HPV16) or 18 E7-pulsed dendritic cells (DC) vaccinations\\u000a were demonstrated in a dose-escalation Phase I clinical trial which enrolled ten patients diagnosed with stage IB or IIA cervical\\u000a cancer (nine HPV 16-positive, one HPV 18-positive). The goal of the study was to define the T-cell epitopes of HPV 16 or 18

  17. PreTect HPV-Proofer: real-time detection and typing of E6/E7 mRNA from carcinogenic human papillomaviruses.

    PubMed

    Molden, Tor; Kraus, Irene; Skomedal, Hanne; Nordstrøm, Trine; Karlsen, Frank

    2007-06-01

    Monitoring human papillomavirus (HPV) E6/E7 mRNA expression may provide an accurate and informative diagnostic approach for detection of oncogene activity related to the development of severe dysplasia or cervical carcinoma. A multiplex nucleic acid sequence based amplification (NASBA) assay, utilizing molecular beacon probes for real-time detection was developed for the identification of E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45. The assay is called PreTect HPV-Proofer and this report describes the development and the analytical performance of the assay. The reproducibility of PreTect HPV-Proofer with regard to a positive result was found to be between 96 and 100%, depending on HPV type. The melting temperature for the different molecular beacons was in the range of 48-55 degrees C, indicating conformational stability, i.e. the molecular beacons will not get activated by the 41 degrees C annealing temperature, but will be activated by the annealing to the target itself. The limit of detection for HPV 16 was ten SiHa or CaSki cells and for HPV 18 one HeLa cell. No cross reactivity was observed with E6/E7 mRNA from the other tested HPV types. mRNA from cervical cells was also successfully amplified after more than one year of storage. In conclusion, the PreTect HPV-Proofer assay, individually identifying E6/E7 mRNA expression from five carcinogenic HPV types, is a reproducible assay that may serve as a valuable tool in monitoring HPV infections producing proteins with a transforming potential. PMID:17379322

  18. The X-link inhibitor of apoptosis protein (XIAP) enhances the survivability of C2E7 hybridoma cells under a serum deprived condition

    Microsoft Academic Search

    B. Tey; K. Yap; A. Ali; W. Tan

    Hybridoma C2E7 cell cultured in a serum deprived condition was only survived not longer than 5 days in a batch culture, whereas for the culture supplemented with 10% of serum showed a far superior proliferation and survivability. The serum supplemented culture was able to survive for more than 9 days in a batch culture and recorded a 6.6 fold increase

  19. Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX™ adjuvant in women with cervical intraepithelial neoplasia

    Microsoft Academic Search

    Ian H. Frazer; Michael Quinn; Jim L. Nicklin; Jeffrey Tan; Lew C. Perrin; Peng Ng; Vivienne M. O’Connor; Olivia White; Ngaire Wendt; Juliet Martin; Jayne M. Crowley; Stirling J. Edwards; Andrew W. McKenzie; Susan V. Mitchell; Darryl W. Maher; Martin J. Pearse; Russell L. Basser

    2004-01-01

    Purpose: Persistent infection of cervical epithelium with “high risk” human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX™ adjuvant (HPV16 Immunotherapeutic) for patients with CIN.

  20. [Human papillomavirus type 16 variant analysis of upstream regulatory region and E6, E7 oncogene from cervical cancer patients in Beijing].

    PubMed

    Xiong, Guang-Wu; Yuan, Yang; Li, Meng; Guo, Hong-Yan; Zhang, Xiao-Wei

    2010-04-01

    To investigate distributional characteristics of mutations of HPV16 upstream regulatory region (URR) and E6 and E7 oncogene in the patients with cervical cancer in Beijing and to explore the potential association between oncogenesis of cervical cancer and HPV variants in this region, cervical cancer tissue from 31 cases with positive HPV16 were subjected to regular DNA extraction procedure. The corresponding primers were then designed to amplify the target sequence of URR, E6 and E7. The PCR products were sequenced and blast analysis against GenBank was carried out to evaluate the gene mutation and identify the phylogenetic branches. Among all the cases studied, URR was found to be the most frequent mutation fragments, followed by E7, and E6 was the most conservative sequence. A total of 8 hot mutation spot was identi-fied, which were URR G7521A (100%), C7435G (96.77%), C24T (45.16%), A7729C (45.16%), G7839A (45.16%), E6 T178G (41.94%), E7 A647G (45.16%), and T846C (45.16%). The most frequent HPV 16 branch was type As (54.84%), followed by type E (45.16%). Our results suggested that the mutations of G7521A, A7729C, G7839A, T178G, T350G, A647G, and G658A were likely to be associated with the enhanced oncogenic potential of HPV16 and oncogenesis of cer-vical cancer. In Beijing area, two major branches of HPV16 were type As and E. This finding provides valuable information for HPV vaccine development and infection treatment. Type As and E variants had different distributions among various ages and clinic stage groups. It might lead to a new explanation for the getting younger trend of cervical cancer. PMID:20423887

  1. Human papillomaviruses and non-melanoma skin cancer.

    PubMed

    McLaughlin-Drubin, Margaret E

    2015-04-01

    Human papillomaviruses (HPVs) infect the squamous epithelium and can induce benign and malignant lesions. To date, more than 200 different HPV types have been identified and classified into five genera, ?, ?, ?, ?, and ?. While high-risk ? mucosal HPVs have a well-established role in cervical carcinoma and a significant percentage of other anogenital tract and oral carcinomas, the biology of the cutaneous ? HPVs and their contribution to non-melanoma skin cancer (NMSC) has been less studied. Although the association of ? HPV infection with NMSC in patients with a rare, genetically determined condition, epidermodysplasia verruciformis has been well established, the role of ? HPV infection with NMSC in the normal population remains controversial. In stark contrast to ? HPV-associated cancers, the presence of the ? HPV genome does not appear to be mandatory for the maintenance of the malignant phenotype. Moreover, the mechanism of action of the ? HPV E6 and E7 oncoproteins differs from the ? HPV oncoproteins. PMID:25843732

  2. Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-?B and MAPK signaling pathways and triggers degradation of AML1ETO oncoprotein in a caspase-3-dependent manner

    Microsoft Academic Search

    L Wang; W-L Zhao; J-S Yan; P Liu; H-P Sun; G-B Zhou; Z-Y Weng; W-L Wu; X-Q Weng; X-J Sun; Z Chen; H-D Sun; S-J Chen

    2007-01-01

    Diterpenoids isolated from Labiatae family herbs have strong antitumor activities with low toxicity. In this study, Eriocalyxin B (EriB), a diterpenoid extracted from Isodon eriocalyx, was tested on human leukemia\\/lymphoma cells and murine leukemia models. Acute myeloid leukemia cell line Kasumi-1 was most sensitive to EriB. Significant apoptosis was observed, concomitant with Bcl-2\\/Bcl-XL downregulation, mitochondrial instability and caspase-3 activation. AML1-ETO

  3. Single-tube multiplex PCR using type-specific E6/E7 primers and capillary electrophoresis genotypes 21 human papillomaviruses in neoplasia

    PubMed Central

    2011-01-01

    Background Human papillomavirus (HPV) E6/E7 type-specific oncogenes are required for cervical carcinogenesis. Current PCR protocols for genotyping high-risk HPV in cervical screening are not standardized and usually use consensus primers targeting HPV capsid genes, which are often deleted in neoplasia. PCR fragments are detected using specialized equipment and extra steps, including probe hybridization or primer extension. In published papers, analytical sensitivity is typically compared with a different protocol on the same sample set. A single-tube multiplex PCR containing type-specific primers was developed to target the E6/E7 genes of two low-risk and 19 high-risk genotypes (HPV6, 11 and 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82) and the resulting short fragments were directly genotyped by high-resolution fluorescence capillary electrophoresis. Results The method was validated using long oligonucleotide templates, plasmid clones and 207 clinical samples of DNA from liquid-based cytology, fresh and formalin-fixed specimens and FTA Microcards® imprinted with cut tumor surfaces, swabbed cervical cancers or ejected aspirates from nodal metastases of head and neck carcinomas. Between one and five long oligonucleotide targets per sample were detected without false calls. Each of the 21 genotypes was detected in the clinical sample set with up to five types simultaneously detected in individual specimens. All 101 significant cervical neoplasias (CIN 2 and above), except one adenocarcinoma, contained E6/E7 genes. The resulting genotype distribution accorded with the national pattern with HPV16 and 18 accounting for 69% of tumors. Rare HPV types 70 and 73 were present as the sole genotype in one carcinoma each. One cervical SCC contained DNA from HPV6 and 11 only. Six of twelve oropharyngeal cancer metastases and three neck metastases of unknown origin bore E6/E7 DNA; all but one were HPV16. One neck aspirate contained atypical squames with HPV26. Analytical sensitivity in dilute plasmid mixes was variable. Conclusions A primer-rich PCR readily detects the E6/E7 oncogenes of 21 HPV types in cellular and fixed tissue specimens. The method is straightforward, robust and reproducible and avoids post-PCR enzymatic and hybridization steps while detecting HPV with high clinical sensitivity in significant HPV-related neoplasia regardless of specimen type. PMID:21241508

  4. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    SciTech Connect

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)] [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)] [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

  5. Alteration of the lipid profile in lymphomas induced by MYC overexpression

    PubMed Central

    Eberlin, Livia S.; Gabay, Meital; Fan, Alice C.; Gouw, Arvin M.; Tibshirani, Robert J.; Felsher, Dean W.; Zare, Richard N.

    2014-01-01

    Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas. PMID:24994904

  6. Intercellular trafficking of the nuclear oncoprotein DEK

    E-print Network

    Ploegh, Hidde

    DEK is a biochemically distinct, conserved nonhistone protein that is vital to global heterochromatin integrity. In addition, DEK can be secreted and function as a chemotactic, proinflammatory factor. Here we show that ...

  7. Diagnostic and prognostic validity of the human papillomavirus E6\\/E7 mRNA test in cervical cytological samples of HC2-positive patients

    Microsoft Academic Search

    Maria Benevolo; Irene Terrenato; Marcella Mottolese; Ferdinando Marandino; Mariantonia Carosi; Francesca Rollo; Livia Ronchetti; Paola Muti; Luciano Mariani; Stefano Sindico; Giuseppe Vocaturo; Amina Vocaturo

    2011-01-01

    The study aimed to assess the clinical utility in identifying CIN2 or worse (CIN2+), of the Pretect HPV-Proofer test for E6\\/E7\\u000a mRNA detection in Hybrid Capture 2 (HC2)-positive patients, who underwent colposcopy. In particular, the study analyzed the\\u000a mRNA test performance as the third test in a subgroup of HC2+ patients with less severe than high-grade squamous intraepithelial\\u000a lesions (HSIL?).

  8. Phosphoproteome dynamics in onset and maintenance of oncogene-induced senescence.

    PubMed

    de Graaf, Erik L; Kaplon, Joanna; Zhou, Houjiang; Heck, Albert J R; Peeper, Daniel S; Altelaar, A F Maarten

    2014-08-01

    Expression of the BRAF(V600E) oncoprotein is known to cause benign lesions, such as melanocytic nevi (moles). Despite the oncogenic function of mutant BRAF, these lesions are arrested by a cell-autonomous mechanism called oncogene-induced senescence. Infrequently, nevi can progress to malignant melanoma, through mechanisms that are incompletely understood. To gain more insight into this vital tumor-suppression mechanism, we performed a mass-spectrometry-based screening of the proteome and phosphoproteome in cycling and senescent cells and in cells with abrogated senescence. Proteome analysis of senescent cells revealed the up-regulation of established senescence biomarkers, including specific cytokines, but also several proteins not previously associated with senescence, including extracellular matrix-interacting. Using both general and targeted phosphopeptide enrichment by Ti(4+)-IMAC and phosphotyrosine antibody enrichment, we identified over 15,000 phosphorylation sites. Among the regulated phosphorylation sites we encountered components of the interleukin, BRAF/MAPK, and CDK-retinoblastoma pathways and several other factors. The extensive proteome and phosphoproteome dataset of BRAF(V600E)-expressing senescent cells provides molecular clues as to how oncogene-induced senescence is initiated, maintained, or evaded, serving as a comprehensive proteomic basis for functional validation. PMID:24961811

  9. Pokemon (FBI-1) interacts with Smad4 to repress TGF-?-induced transcriptional responses.

    PubMed

    Yang, Yutao; Cui, Jiajun; Xue, Feng; Zhang, Chuanfu; Mei, Zhu; Wang, Yue; Bi, Mingjun; Shan, Dapeng; Meredith, Alex; Li, Hui; Xu, Zhi-Qing David

    2015-03-01

    Pokemon, an important proto-oncoprotein, is a transcriptional repressor that belongs to the POK (POZ and Krüppel) family. Smad4, a key component of TGF-? pathway, plays an essential role in TGF-?-induced transcriptional responses. In this study, we show that Pokemon can interact directly with Smad4 both in vitro and in vivo. Overexpression of Pokemon decreases TGF-?-induced transcriptional activities, whereas knockdown of Pokemon increases these activities. Interestingly, Pokemon does not affect activation of Smad2/3, formation of Smads complex, or DNA binding activity of Smad4. TGF-?1 treatment increases the interaction between Pokemon and Smad4, and also enhances the recruitment of Pokemon to Smad4-DNA complex. In addition, we also find that Pokemon recruits HDAC1 to Smad4 complex but decreases the interaction between Smad4 and p300/CBP. Taken together, all these data suggest that Pokemon is a new partner of Smad4 and plays a negative role in TGF-? pathway. PMID:25514493

  10. HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway

    PubMed Central

    Xue, Min; Yao, Shuihong; Hu, Minmin; Li, Wan; Hao, Tingting; Zhou, Feng; Zhu, Xiaofei; Lu, Hongmei; Qin, Di; Yan, Qin; Zhu, Jianzhong; Gao, Shou-Jiang; Lu, Chun

    2014-01-01

    Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV). Although the interaction between HIV-1 and KSHV plays a pivotal role in promoting the aggressive manifestations of KS, the pathogenesis underlying AIDS-KS remains largely unknown. Here we examined HIV-1 Nef protein promotion of KSHV oncoprotein K1-induced angiogenesis. We showed that both internalized and ectopic expression of Nef in endothelial cells synergized with K1 to facilitate vascular tube formation and cell proliferation, and enhance angiogenesis in a chicken CAM model. In vivo experiments further indicated that Nef accelerated K1-induced angiogenesis and tumorigenesis in athymic nu/nu mice. Mechanistic studies revealed that Nef and K1 synergistically activated PI3K/AKT/mTOR signaling by downregulating PTEN. Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3? UTR of its mRNA. Inhibition of miR-718 expression increased PTEN synthesis and suppressed the synergistic effect of Nef- and K1-induced angiogenesis and tumorigenesis. These results indicate that, by targeting PTEN, miR-718 mediates Nef- and K1-induced angiogenesis via activation of AKT/mTOR signaling. Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target. PMID:25104021

  11. Ligand binding to heme proteins: III. FTIR studies of His-E7 and Val-E11 mutants of carbonmonoxymyoglobin.

    PubMed Central

    Braunstein, D. P.; Chu, K.; Egeberg, K. D.; Frauenfelder, H.; Mourant, J. R.; Nienhaus, G. U.; Ormos, P.; Sligar, S. G.; Springer, B. A.; Young, R. D.

    1993-01-01

    Fouier-transform infrared (FTIR) difference spectra of several His-E7 and Val-E11 mutants of sperm whale carbonmonoxymyoglobin were obtained by photodissociation at cryogenic temperatures. The IR absorption of the CO ligand shows characteristic features for each of the mutants, both in the ligand-bound (A) state and in the photodissociated (B) state. For most of the mutants, a single A substate band is observed, which points to the crucial role of the His-E7 residue in determining the A substrate spectrum of the bound CO in the native structure. The fact that some of the mutants show more than one stretch band of the bound CO indicates that the appearance of multiple A substates is not exclusively connected to the presence of His-E7. In all but one mutant, multiple stretch bands of the CO in the photodissociated state are observed; these B substates are thought to arise from discrete positions and/or orientations of the photodissociated ligand in the heme pocket. The red shifts of the B bands with respect to the free-gas frequency indicate weak binding in the heme pocket. The observation of similar red shifts in microperoxidase (MP-8), where there is no residue on the distal side, suggests that the photodissociated ligand is still associated with the heme iron. Photoselection experiments were performed to determine the orientation of the bound ligand with respect to the heme normal by photolyzing small fractions of the sample with linearly polarized light at 540 nm. The resulting linear dichroism in the CO stretch spectrum yielded angles alpha > 20 degrees between the CO molecular axis and the heme normal for all of the mutants. We conclude that the off-axis position of the CO ligand in the native structure does not arise from steric constraints imposed by the distal histidine. There is no clear correlation between the size of the distal residue and the alpha of the CO ligand. PMID:8312483

  12. Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis.

    PubMed

    Lin, Yi-Te; Lu, Hsing-Pang; Chao, Chuck C-K

    2015-01-01

    Prothymosin alpha (PTMA) is overexpressed in various human tumors, including hepatocellular carcinoma (HCC). The significance of PTMA overexpression and its underlying mechanism remain unclear. We show here that silencing PTMA sensitizes HCC cells to the kinase inhibitor sorafenib. In contrast, ectopic expression of PTMA induces cell resistance to the drug. While inhibitors targeting JNK, ERK or PI3K reduce PTMA expression, only ERK activation is suppressed by sorafenib. In addition, inhibition of ERK produces a dramatic decrease in both endogenous PTMA level and promoter activation. Ectopic expression of active MKK1/2 considerably induces PTMA expression. We also identify a sorafenib-responsive segment lying 1000-1500-bp upstream of the PTMA transcription start site and observe that it is controlled by c-Myc and ERK. Mutation in the PTMA promoter at the predicted c-Myc binding site and silencing of c-Myc both abrogate sorafenib's effect on PTMA transcription. We also find that silencing PTMA potentiates Bax translocation to mitochondria in response to sorafenib and this is associated with increased cytochrome c release from mitochondria and enhanced caspase-9 activation. These results indicate that PTMA is positively regulated by the oncoprotein c-Myc and protects HCC cells against sorafenib-induced cell death, thus identifying PTMA as a new target for chemotherapy against HCC. PMID:25451688

  13. Proton electron nuclear double resonance from nitrosyl horse heart myoglobin: the role of His-E7 and Val-E11.

    PubMed Central

    Flores, M; Wajnberg, E; Bemski, G

    2000-01-01

    Electron nuclear double resonance (ENDOR) spectroscopy has been used to study protons in nitrosyl horse heart myoglobin (MbNO). (1)H ENDOR spectra were recorded for different settings of the magnetic field. Detailed analysis of the ENDOR powder spectra, using computer simulation, based on the "orientation-selection" principle, leads to the identification of the available protons in the heme pocket. We observe hyperfine interactions of the N(HisF8)-Fe(2+)-N(NO) complex with five protons in axial and with eight protons in the rhombic symmetry along different orientations, including those of the principal axes of the g-tensor. Protons from His-E7 and Val-E11 residues are identified in the two symmetries, rhombic and axial, exhibited by MbNO. Our results indicate that both residues are present inside the heme pocket and help to stabilize one particular conformation. PMID:10733988

  14. Amino Acid Insertion Reveals a Necessary Three-Helical Intermediate in the Folding Pathway of the Colicin E7 Immunity Protein Im7

    PubMed Central

    Knowling, Stuart E.; Figueiredo, Angelo Miguel; Whittaker, Sara B.-M.; Moore, Geoffrey R.; Radford, Sheena E.

    2009-01-01

    The small (87-residue) ?-helical protein Im7 (an inhibitor protein for colicin E7 that provides immunity to cells producing colicin E7) folds via a three-state mechanism involving an on-pathway intermediate. This kinetic intermediate contains three of four native helices that are oriented in a non-native manner so as to minimise exposed hydrophobic surface area at this point in folding. The short (6-residue) helix III has been shown to be unstructured in the intermediate ensemble and does not dock onto the developing hydrophobic core until after the rate-limiting transition state has been traversed. After helix III has docked, it adopts an ?-helical secondary structure, and the side chains of residues within this region provide contacts that are crucial to native-state stability. In order to probe further the role of helix III in the folding mechanism of Im7, we created a variant that contains an eight-amino-acid polyalanine-like helix stabilised by a Glu-Arg salt bridge and an Asn-Pro-Gly capping motif, juxtaposed C-terminal to the natural 6-residue helix III. The effect of this insertion on the structure of the native protein and its folding mechanism were studied using NMR and ?-value analysis, respectively. The results reveal a robust native structure that is not perturbed by the presence of the extended helix III. Mutational analysis performed to probe the folding mechanism of the redesigned protein revealed a conserved mechanism involving the canonical three-helical intermediate. The results suggest that folding via a three-helical species stabilised by both native and non-native interactions is an essential feature of Im7 folding, independent of the helical propensity of helix III. PMID:19651139

  15. Human papillomavirus immortalization and transformation functions

    Microsoft Academic Search

    Karl Münger; Peter M Howley

    2002-01-01

    The high risk HPVs (such as HPV-16 and HPV-18) that are associated with specific anogenital cancers encode two oncoproteins E6 and E7, which are expressed in the HPV positive cancers. The E7 protein functions in cellular transformation, at least in part, through interactions with pRB and the other pRB related ‘pocket proteins’. The major target of the E6 oncoprotein encoded

  16. Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state

    PubMed Central

    Rounbehler, Robert J.; Fallahi, Mohammad; Yang, Chunying; Steeves, Meredith A.; Li, Weimin; Doherty, Joanne R.; Schaub, Franz X.; Sanduja, Sandhya; Dixon, Dan A.; Blackshear, Perry J.; Cleveland, John L.

    2012-01-01

    SUMMARY Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis. PMID:22863009

  17. HCCR-1, a novel oncogene, encodes a mitochondrial outer membrane protein and suppresses the UVC-induced apoptosis

    PubMed Central

    Cho, Goang-Won; Shin, Seung Min; Kim, Hyun Kee; Ha, Seon-Ah; Kim, Sanghee; Yoon, Joo-Hee; Hur, Soo Young; Kim, Tae Eung; Kim, Jin Woo

    2007-01-01

    Background The Human cervical cancer oncogene (HCCR-1) has been isolated as a human oncoprotein, and has shown strong tumorigenic features. Its potential role in tumorigenesis may result from a negative regulation of the p53 tumor suppressor gene. Results To investigate the biological function of HCCR-1 in the cell, we predicted biological features using bioinformatic tools, and have identified a LETM1 homologous domain at position 75 to 346 of HCCR-1. This domain contains proteins identified from diverse species predicted to be mitochondrial proteins. Fluorescence microscopy and fractionation experiments showed that HCCR-1 is located in mitochondria in the COS-7, MCF-7 and HEK/293 cell lines, and subcompartamentally at the outer membrane in the HEK/293 cell line. The topological structure was revealed as the NH2-terminus of HCCR-1 oriented toward the cytoplasm. We also observed that the D1-2 region, at position 1 to 110 of HCCR-1, was required and sufficient for posttranslational mitochondrial import. The function of HCCR-1 on mitochondrial membrane is to retard the intrinsic apoptosis induced by UVC and staurosporine, respectively. Conclusion Our experiments show the biological features of HCCR-1 in the cell, and suggest that uncontrolled expression of HCCR-1 may cause mitochondrial dysfunction that can result in resisting the UVC or staurosporine-induced apoptosis and progressing in the tumor formation. PMID:18045496

  18. Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration

    PubMed Central

    Endo, Kazuhira; Kondo, Satoru; Shackleford, Julia; Horikawa, Toshiyuki; Kitagawa, Noriko; Yoshizaki, Tomokazu; Furukawa, Mitsuru; Zen, Yoh; Pagano, Joseph S.

    2009-01-01

    Tumor metastasis is a complex phenomenon that is the culmination of effects of numerous cellular factors. We have shown that the EBV oncoprotein, latent membrane protein 1 (LMP1), is capable of inducing a wide range of such factors in cell culture, expression of which is also elevated in the LMP1-expressing tumor, nasopharyngeal carcinoma (NPC), a highly invasive neoplasm. Recently, the membrane-crosslinker protein ezrin has been implicated in tumor cell metastasis and malignant progression. In this study, we evaluated the possible role of LMP1 and ezrin in the pathophysiology of NPC. We show that C-terminal phosphorylation of ezrin is increased by expression of LMP1 in nasopharyngeal (NP) cells through a Protein Kinase C (PKC) pathway. LMP1 enhances organization of a ternary complex of CD44, ezrin and F-actin which is a prerequisite for ezrin phosphorylation. In NPC tissues, expression of phosphoezrin and LMP1 is directly correlated. Silencing of endogenously expressed ezrin suppresses LMP1-induced cell motility and invasiveness. Moreover inhibition of ezrin phosphorylation by PKC inhibitor suppresses migration and invasion of NP cells. These data demonstrate that phosphorylation of ezrin and its recruitment to the cell membrane linked to F-actin and CD44 is a process required for LMP1-stimulated cell motility and invasion of NP cells. PMID:19234486

  19. Posttranscriptional repression of the cel gene of the ColE7 operon by the RNA-binding protein CsrA of Escherichia coli.

    PubMed

    Yang, Tsung-Yeh; Sung, Yun-Min; Lei, Guang-Sheng; Romeo, Tony; Chak, Kin-Fu

    2010-07-01

    Carbon storage regulator (CsrA) is a eubacterial RNA-binding protein that acts as a global regulator of many functionally diverse chromosomal genes. Here, we reveal that CsrA represses expression from an extrachromosomal element of Escherichia coli, the lysis gene (cel) of the ColE7 operon (cea-cei-cel). This operon and colicin expression are activated upon SOS response. Disruption of csrA caused approximately 5-fold increase of the lysis protein. Gel mobility shift assays established that both the single-stranded loop of the T1 stem-loop distal to cei, and the putative CsrA binding site overlapping the Shine-Dalgarno sequence (SD) of the cel gene are important for CsrA binding. Substitution mutations at SD relieved CsrA-dependent repression of the cel gene in vivo. Steady-state levels and half-life of the cel mRNA were not affected by CsrA, implying that regulation is mediated at the translational level. Levels of CsrB and CsrC sRNAs, which bind to and antagonize CsrA, were drastically reduced upon induction of the SOS response, while the CsrA protein itself remained unaffected. Thus, CsrA is a trans-acting modulator that downregulates the expression of lysis protein, which may confer a survival advantage on colicinogenic E. coli under environment stress conditions. PMID:20378712

  20. Behavioral and electrophysiological activity of (Z,E)-7,9,11-dodecatrienyl formate, a mimic of the major sex pheromone component of carob moth,Ectomyelois ceratoniae.

    PubMed

    Todd, J L; Millar, J G; Vetter, R S; Baker, T C

    1992-12-01

    The behavioral and electrophysiological activity of a mimic [(Z,E)7,9,11-dodecatrienyl formate] of the major sex pheromone component [(Z,E) 9,11,13-tetradecatrienal] of carob moth was assessed. Wind-tunnel bioassays demonstrated that the formate was as effective as natural gland extracts, and significantly more effective than the trienal alone or than the trienal blended with two minor pheromone components, in evoking source contact. Dispensers containing the formate were as effective as trienal-containing blend lures in attracting males when placed at the same dosage in traps in date gardens. Single-cell recordings showed that at least two olfactory neurons, differentiated by spike amplitude, are located in the long trichoid hairs on male carob moth antennae. Dose-response relationships indicated that puffs from cartridges loaded with at least 0.1 ?g of the formate or of the trienal were necessary to elicit spiking by either the small or the large-spiking cell within a sensillum. Cross-adaptation studies demonstrated that both compounds stimulated the same large-spiking cell. The frequencies of spikes evoked from the large cell when stimulated by emissions from 0.1-?g, 1-?g, or 10-?g cartridges of either the formate or the trienal were not significantly different, suggesting that the formate is an effective mimic of the trienal at the antennal receptor cell level. PMID:24254874

  1. An alternatively spliced IL-15 isoform modulates abrasion-induced keratinocyte activation.

    PubMed

    Lee, Tsung-Lin; Chang, Mei-Ling; Lin, Yu-Jei; Tsai, Ming-Hsun; Chang, Yi-Hsuan; Chuang, Che-Ming; Chien, Yun; Sosinowski, Tomasz; Wang, Chih-Hsiu; Chen, Yi-Yuan; Lee, Chien-Kuo; Chen, Jau-Shiuh; Wang, Li-Fang; Kung, John T; Ku, Chia-Chi

    2015-05-01

    In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 (deficient memory (DM)) of N-ethyl-N-nitrosourea mutagenized mice. The DM epidermis expressed an alternatively spliced IL-15 mRNA isoform, IL-15?E7, and a wild-type (WT) IL-15 isoform at comparable levels. Mechanical stimulation of DM skin or DM skin graft transplanted onto the WT host resulted in reduced keratinocyte activation and inhibition of neutrophil infiltration into the dermis, demonstrating that DM keratinocytes produced less inflammatory response to external stimulation. Ectopic expression of IL-15?E7 in WT skin prevented abrasion-induced epidermal thickening, blocked the accumulation of nuclear antigen Ki67(+) cells in the basal and the suprabasal cell layers, increased loricrin expression, and also increased keratinocyte CXCL1 and G-CSF production. IL-15?E7 also profoundly blocked neutrophil infiltration in SDS- or immiquimod (IMQ)-treated WT skin. Recombinant IL-15?E7 failed to activate STAT-5 and its downstream target bcl-2 expression. Our study points to IL-15?E7 as a potential therapeutic agent for treating neutrophilia-associated inflammatory skin disorders. PMID:25615554

  2. Sequential Cisplatin Therapy and Vaccination with HPV16 E6E7L2 Fusion Protein in Saponin Adjuvant GPI-0100 for the Treatment of a Model HPV16+ Cancer

    PubMed Central

    Peng, Shiwen; Wang, Joshua W.; Karanam, Balasubramanyam; Wang, Chenguang; Huh, Warner K.; Alvarez, Ronald D.; Pai, Sara I.; Hung, Chien-fu; Wu, T. -C.; Roden, Richard B. S.

    2015-01-01

    Clinical studies suggest that responses to HPV16 E6E7L2 fusion protein (TA-CIN) vaccination alone are modest, and GPI-0100 is a well-tolerated, potent adjuvant. Here we sought to optimize both the immunogenicity of TA-CIN via formulation with GPI-0100 and treatment of HPV16+ cancer by vaccination after cisplatin chemotherapy. HPV16 neutralizing serum antibody titers, CD4+ T cell proliferative and E6/E7-specific CD8+ T cell responses were significantly enhanced when mice were vaccinated subcutaneously (s.c.) or intramuscularly (i.m.) with TA-CIN formulated with GPI-0100. Vaccination was tested for therapy of mice bearing syngeneic HPV16 E6/E7+ tumors (TC-1) either in the lung or subcutaneously. Mice treated with TA-CIN/GPI-0100 vaccination exhibited robust E7-specific CD8+ T cell responses, which were associated with reduced tumor burden in the lung, whereas mice receiving either component alone were similar to controls. Since vaccination alone was not sufficient for cure, mice bearing s.c. TC-1 tumor were first treated with two doses of cisplatin and then vaccinated. Vaccination with TA-CIN/GPI-0100 i.m. substantially retarded tumor growth and extended survival after cisplatin therapy. Injection of TA-CIN alone, but not GPI-0100, into the tumor (i.t.) was similarly efficacious after cisplatin therapy, but the mice eventually succumbed. However, tumor regression and extended remission was observed in 80% of the mice treated with cisplatin and then intra-tumoral TA-CIN/GPI-0100 vaccination. These mice also exhibited robust E7-specific CD8+ T cell and HPV16 neutralizing antibody responses. Thus formulation of TA-CIN with GPI-0100 and intra-tumoral delivery after cisplatin treatment elicits potent therapeutic responses in a murine model of HPV16+ cancer. PMID:25560237

  3. Deficiencies in the Fanconi anemia DNA damage response pathway increase sensitivity to HPV-associated head and neck cancer.

    PubMed

    Park, Jung Wook; Pitot, Henry C; Strati, Katerina; Spardy, Nicole; Duensing, Stefan; Grompe, Markus; Lambert, Paul F

    2010-12-01

    Patients with the rare genetic disease, Fanconi anemia (FA), are highly susceptible to squamous cell carcinomas arising at multiple anatomic sites including the head and neck region. Human papillomaviruses (HPVs), particularly HPV16, are associated with ?20% of head and neck squamous cell carcinomas (HNSCCs) in the general population. Some but not other investigators have reported that HNSCCs in FA patients are much more frequently positive for HPV. In addition, studies have demonstrated an interaction between the HPV16 E7 oncoprotein and the FA pathway, a DNA damage response pathway deficient in FA patients. On the basis of these studies, it was hypothesized that the FA pathway contributes to repair of DNA damage induced by HPV16 E7, providing one explanation for why FA patients are predisposed to HPV-associated HNSCCs. To determine the importance of the FA pathway in modulating the oncogenic abilities of E7, we crossed K14E7 transgenic (K14E7) and fancD2 knockout mice (FancD2(-/-)) to establish K14E7/FancD2(-/-) and K14E7/FancD2(+/+) mice and monitored their susceptibility to HNSCC when treated with a chemical carcinogen. K14E7/FancD2(-/-) mice had a significantly higher incidence of HNSCC compared with K14E7/FancD2(+/+) mice. This difference correlated with an increased proliferative index and the increase in expression of biomarkers that are used to assess levels of DNA damage. These animal studies support the hypotheses that FA patients have increased susceptibility to HPV-associated cancer and that the FA DNA damage response pathway normally attenuates the oncogenic potential of HPV16 E7. PMID:20935219

  4. Xanthorrhizol induces apoptosis via the up-regulation of bax and p53 in HeLa cells.

    PubMed

    Ismail, Norzila; Pihie, Azimahtol Hawariah Lope; Nallapan, Meenakshii

    2005-01-01

    Xanthorrhizol is a sesquiterpenoid compound extracted from Curcuma xanthorrhiza, which is known locally as Temulawak. Traditionally, C. xanthorrhiza was found to have antibacterial, anticancer and anti-inflammatory activity. The rhizome has also been used to treat inflammation in postpartum uterine bleeding. An antiproliferative assay using methylene blue staining revealed that xanthorrhizol inhibited the proliferation of the cervical cancer cell line HeLa with an EC50 value of 6.16 microg/ml. Xanthorrhizol significantly increased apoptosis in HeLa cells, as evaluated by the Tdt-mediated dUTP nick end-labelling (TUNEL) assay and nuclear morphology by Hoechst 33258 staining. Western blot analysis, which was further confirmed by the immunostaining results, implied an up-regulation of tumor suppressor protein p53 and the pro-apoptotic protein Bax, following the treatment with xanthorrhizol. Xanthorrhizol, however, did not affect the expression of the anti-apoptotic protein, Bcl-2 and the viral oncoprotein, E6. Hence, xanthorrhizol is a promising antiproliferative and anticancer agent which induces p53 and Bax-dependent apoptosis in HeLa cervical cancer cells. PMID:16158967

  5. c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

    PubMed Central

    Sledziona, James; Cibull, Michael L.; Wang, Chi; Richards, Dana L.; Neltner, Janna M.; Beach, Carol; McCorkle, Joseph R.; Kaetzel, David M.; Plattner, Rina

    2014-01-01

    Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression. PMID:24096484

  6. HMGA2 induces epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells

    PubMed Central

    LUO, YIZHOU; LI, WENFENG; LIAO, HUI

    2013-01-01

    Epithelial-to-mesenchymal transition (EMT) is an important event during tumorigenesis. The human high-mobility group A2 (HMGA2) is a chromatin-binding protein, which contains three AT-hook domains that enable its binding to the minor groove of DNA. HMGA2 organizes protein complexes on enhancers of various genes to regulate gene expression and cell differentiation. The HMGA2 protein has been reported to be overexpressed in many types of cancer. It is not known, however, whether HMGA2 regulates EMT in human hepatocellular carcinoma (HCC) cell lines, and the mechanism(s) have not been fully elucidated. In this study, the expression of HMGA2 in five HCC cell lines was examined. The levels of HMGA2 expression among the five HCC cell lines coincided with their invasiveness. The variation in HMGA2 expression significantly correlated with the expression of several putative EMT markers. In addition, assessment of the invasive potential, following transfection with HMGA2-siRNA, demonstrated that the rate of cell migration was significantly reduced, suggesting that HMGA2 may be an important contributor to the invasion of tumor cells and that expression levels of HMGA2 influence the metastatic behavior of HCC cells. To further confirm the conclusion and explore the molecular mechanism through which HMGA2 induces EMT, we found that HMGA2 upregulates the expression of Twist and Snail in HCC cell lines. In conclusion, this present study is the first to show that HMGA2 effectively regulates EMT to induce invasion and metastasis in HCC cells. The function of HMGA2 as an oncoprotein may be associated with several important molecules involved in invasion and metastasis of cancer cells. PMID:23599793

  7. Electrochemical quartz crystal microbalance, voltammetry, spectroelectrochemical, and microscopic studies of adsorption behavior for (7E,7â²Z)-diphenyl-7,7â²-diapocarotene electrochemical oxidation product

    Microsoft Academic Search

    Guoqiang Gao; David B. Wurm; Yeon-Taik Kim; Lowell D. Kispert

    1997-01-01

    Polymeric products, which are formed by reaction of the dications of (7E,7â²Z)-diphenyl-7,7â²-diapocarotene (I) generated by electrochemical oxidation in dichloromethane with the neutral carotenoid, are adsorbed on various electrode surfaces. An apparent average molar mass of 5400 g\\/(mol electrons) was calculated from simultaneous electrochemical quartz crystal microbalance (EQCM) measurements, and the green, fiber-like structure observed by optical microscopy confirms the formation

  8. Phase I\\/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein–based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia

    Microsoft Academic Search

    Sophie Hallez; Philippe Simon; Frédéric Maudoux; Jean Doyen; Jean-Christophe Noël; Aude Beliard; Xavier Capelle; Frédéric Buxant; Isabelle Fayt; Anne-Cécile Lagrost; Pascale Hubert; Colette Gerday; Arsène Burny; Jacques Boniver; Jean-Michel Foidart; Philippe Delvenne; Nathalie Jacobs

    2004-01-01

    Purpose: Infection with oncogenic human papillomavirus (HPV) and HPV-16 in particular is a leading cause of anogenital neoplasia. High-grade intraepithelial lesions require treatment because of their potential to progress to invasive cancer. Numerous preclinical studies have demonstrated the therapeutic potential of E7-directed vaccination strategies in mice tumour models. In the present study, we tested the immunogenicity of a fusion protein

  9. Regression of Cervical Intraepithelial Neoplasia and Loss of Human Papillomavirus (HPV) Infection Is Associated with Cell-mediated Immune Responses to an HPV Type 16 E7 Peptide1

    Microsoft Academic Search

    Anna S. Kadish; Patrick Timmins; Yuexian Wang; Gloria Y. F. Ho; Robert D. Burk; John Ketz; Seymour L. Romney; Anne Johnson; Ruth Angeletti; Maria Abadi

    Most human papillomavirus (HPV)-associated cervical intraepithelial neoplasia (CIN) lesions in normal women regress spontaneously, but a small number persist and may progress to invasive cancer. To evaluate the role of immunity to HPV and the outcome of CIN and associated HPV infection, we examined cell-mediated immune (CMI) responses to HPV 16 E6 and E7 peptides. One hundred thirty-six women with

  10. Coadministration of the fungal immunomodulatory protein FIP-Fve and a tumour-associated antigen enhanced antitumour immunity

    PubMed Central

    Ding, Ying; Seow, See Voon; Huang, Chiung Hui; Liew, Lee Mei; Lim, Yaw Chyn; Kuo, I Chun; Chua, Kaw Yan

    2009-01-01

    Fve is a fungal protein isolated from the golden needle mushroom Flammulina velutipes and has previously been reported to trigger immunological responses in both mouse and human lymphocytes. In this study, we evaluated the potential application of Fve as an adjuvant for tumour immunotherapy and examined the underlying mechanism(s). When the human papillomavirus (HPV)-16 E7 oncoprotein was used as a model antigen, mice coimmunized with HPV-16 E7 and Fve showed enhanced production of HPV-16 E7-specific antibodies as well as expansion of HPV-16 E7-specific interferon (IFN)-?-producing CD4+ and CD8+ T cells as compared with mice immunized with HPV-16 E7 alone. Tumour protection assays showed that 60% of mice coimmunized with HPV-16 E7 plus Fve, as compared with 20% of those immunized only with HPV-16 E7, remained tumour-free for up to 167 days after challenge with the tumour cells. Tumour therapeutic assays showed that HPV-16 E7 plus Fve treatment significantly prolonged the survival of tumour-bearing mice as compared with those treated only with HPV-16 E7. In vivo cell depletion and adoptive T-cell transfer assays showed that CD4+ and CD8+ T cells and IFN-? played critical roles in conferring the antitumour effects. Interestingly, Fve could stimulate the maturation of splenic dendritic cells in vivo and induce antigen-specific CD8+ T-cell immune responses. In summary, Fve has potent adjuvant properties that enhance T helper type 1 antigen-specific humoral and cellular immune responses which confer strong antitumour effects. The use of Fve as an adjuvant could be an attractive alternative to the current vaccination strategy for cancer immunotherapy. PMID:19740349

  11. Diagnostic performance of HPV E6/E7, hTERT, and Ki67 mRNA RT-qPCR assays on formalin-fixed paraffin-embedded cervical tissue specimens from women with cervical cancer.

    PubMed

    Wang, Hye-Young; Kim, Geehyuk; Cho, Hyemi; Kim, Sunghyun; Lee, Dongsup; Park, Sunyoung; Park, Kwang Hwa; Lee, Hyeyoung

    2015-06-01

    Human papillomavirus (HPV) is a major cause of cervical cancer, which is the third most common cancer in women. Human telomerase reverse transcriptase (hTERT) and Ki67 are tumor cell markers indicating cancer cell proliferation in cancer patients, and activation of hTERT and Ki67 leads to progressive cervical carcinogenesis. In the present study, we evaluated the CervicGen HPVE6/E7 mRNA RT-qDx assay, which detects 16 HPV high-risk (HR) genotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68 and 69), and the CervicGen hTERT and Ki67 mRNA RT-qDx assay using 117 formalin-fixed paraffin-embedded (FFPE) cervical cancer tissue samples. The diagnostic validity of the CervicGen HPV RT-qDx assay for detecting histologically proven prevalent squamous cell carcinoma (SCC) was 94% sensitivity, 100% specificity, 77.8% positive predictive value (PPV), and 78.9% negative predictive value (NPV). The most common HPV genotypes detected in FFPE cervical cancer tissue samples were HPV 16 (56%) and HPV 18 (10%). The positivity rate of hTERT and Ki67 mRNA expressions in FFPE cervical cancer tissue samples on RT-qPCR was 65% and 93% respectively. Moreover, the positivity rates were 92% for a combination of HPV E6/E7 and hTERT mRNA expressions, 97% for HPV E6/E7 and Ki67 mRNA expressions, and 99% (99/100) for the combination of HPV E6/E7, hTERT, and Ki67 mRNA expressions. These data showed that SSC FFPE cervical cancer tissue samples correlated more strongly with high Ki67 mRNA expressions than with hTERT mRNA expressions. Notably, hTERT and Ki67 mRNA expression level was increased in high-grade cervical lesions, but was very low in normal samples. Our findings suggest that the combination of HPV E6/E7, hTERT, and Ki67 mRNA expression levels could be used in a complementary manner in diagnosing high-grade cervical lesions. Further studies are required to evaluate these assays as a useful predictive tool for screening low-grade cervical lesions. PMID:25835783

  12. Relationship between HPV 16, 18, 31, 33, 45 DNA detection and quantitation and E6/E7 mRNA detection among a series of cervical specimens with various degrees of histological lesions.

    PubMed

    Baron, Carolina; Henry, Mireille; Tamalet, Catherine; Villeret, Julia; Richet, Herve; Carcopino, Xavier

    2015-08-01

    Better understanding of the correlation between high-risk HPV DNA testing, viral load quantitation, and E6/E7 mRNA detection is required. The aim of this study was to assess the relationship between these markers and the severity of cervical lesions. One-hundred and fifty one directed cervical specimens were analysed (normal, cervical intraepithelial neoplasia, and cancer). HPV types 16, 18, 31, 33, and 45 DNA detection and quantititation and E6/E7 mRNA detection were performed. DNA was detected in 87 (57.6%) samples and increased from 0% (normal) to 93.9% (cancer). E6/E7 mRNA was detected in 65 (43%) samples and increased with the severity of the lesions from 0% (normal) to 78.8% (26/33) (cancers) (P?E7 mRNA detection were compared in the 141 samples harbouring HPV16, 18, 31, 33, or 45 infection: 45.4% (64/141) of specimens were DNA-/mRNA-, 46% (65/141) were DNA?+?/mRNA+ and 8.5% (12/141) were DNA?+?/mRNA-. The proportion of DNA?+?/mRNA+ specimens increased with the severity of the lesions (P?E7 mRNA detection and concordant DNA?+?/mRNA+ detection increases with the severity of the lesions and with the HPV DNA load. J. Med. Virol. 87:1389-1396, 2015. © 2015 Wiley Periodicals, Inc. PMID:25908062

  13. Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase ?-subunit gene expression by miRNA.

    PubMed

    Zhang, Yong-Mei; Noto, Jennifer M; Hammond, Charles E; Barth, Jeremy L; Argraves, W Scott; Backert, Steffen; Peek, Richard M; Smolka, Adam J

    2014-04-01

    Acute Helicobacter pylori infection of gastric epithelial cells induces CagA oncoprotein- and peptidoglycan (SLT)-dependent mobilization of NF-?B p50 homodimers that bind to H-K-ATPase ?-subunit (HK?) promoter and repress HK? gene transcription. This process may facilitate gastric H. pylori colonization by induction of transient hypochlorhydria. We hypothesized that H. pylori also regulates HK? expression posttranscriptionally by miRNA interaction with HK? mRNA. In silico analysis of the HK? 3' untranslated region (UTR) identified miR-1289 as a highly conserved putative HK?-regulatory miRNA. H. pylori infection of AGS cells transfected with HK? 3' UTR-Luc reporter construct repressed luciferase activity by 70%, whereas ?cagA or ?slt H. pylori infections partially abrogated repression. Transfection of AGS cells expressing HK? 3' UTR-Luc construct with an oligoribonucleotide mimetic of miR-1289 induced maximal repression (54%) of UTR activity within 30 min; UTR activity was unchanged by nontargeting siRNA transfection. Gastric biopsies from patients infected with cagA(+) H. pylori showed a significant increase in miR-1289 expression compared with uninfected patients or those infected with cagA(-) H. pylori. Finally, miR-1289 expression was necessary and sufficient to attenuate biopsy HK? protein expression in the absence of infection. Taken together, these data indicate that miR-1289 is upregulated by H. pylori in a CagA- and SLT-dependent manner and targets HK? 3' UTR, affecting HK? mRNA translation. The sensitivity of HK? mRNA 3' UTR to binding of miR-1289 identifies a novel regulatory mechanism of gastric acid secretion and offers new insights into mechanisms underlying transient H. pylori-induced hypochlorhydria. PMID:24503769

  14. Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors

    PubMed Central

    Wichmann, C; Quagliano-Lo Coco, I; Yildiz, Ö; Chen-Wichmann, L; Weber, H; Syzonenko, T; Döring, C; Brendel, C; Ponnusamy, K; Kinner, A; Brandts, C; Henschler, R; Grez, M

    2015-01-01

    The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo. CD34+ cells expressing both oncogenes resemble the AML-M2 myeloblastic cell phenotype, in contrast to REtr-expressing cells which largely undergo granulocytic differentiation. Oncogenic c-KIT amplifies REtr-depended clonogenic growth and protects cells from exhaustion. Activated c-KIT reverts REtr-induced DNA damage and apoptosis. In the presence of activated c-KIT, REtr-downregulated DNA-repair genes are re-expressed leading to an enhancement of DNA-repair efficiency via homologous recombination. Together, our results provide new mechanistic insight into REtr and c-KIT oncogenic cooperativity and suggest that augmented DNA repair accounts for the increased chemoresistance observed in t(8;21)-positive AML patients with activated c-KIT mutations. This cell-protective mechanism might represent a new therapeutic target, as REtr cells with activated c-KIT are highly sensitive to pharmacological inhibitors of DNA repair. PMID:24897507

  15. Chromogenic In Situ Hybridization and p16/Ki67 Dual Staining on Formalin-Fixed Paraffin-Embedded Cervical Specimens: Correlation with HPV-DNA Test, E6/E7 mRNA Test, and Potential Clinical Applications

    PubMed Central

    Zappacosta, Roberta; Colasante, Antonella; Viola, Patrizia; D'Antuono, Tommaso; Lattanzio, Giuseppe; Capanna, Serena; Gatta, Daniela Maria Pia; Rosini, Sandra

    2013-01-01

    Although HPV-DNA test and E6/E7 mRNA analyses remain the current standard for the confirmation of human papillomavirus (HPV) infections in cytological specimens, no universally adopted techniques exist for the detection of HPV in formalin-fixed paraffin-embedded samples. Particularly, in routine laboratories, molecular assays are still time-consuming and would require a high level of expertise. In this study, we investigated the possible use of a novel HPV tyramide-based chromogenic in situ hybridization (CISH) technology to locate HPV on tissue specimens. Then, we evaluate the potential usefulness of p16INK4a/Ki-67 double stain on histological samples, to identify cervical cells expressing HPV E6/E7 oncogenes. In our series, CISH showed a clear signal in 95.2% of the specimens and reached a sensitivity of 86.5%. CISH positivity always matched with HPV-DNA positivity, while 100% of cases with punctated signal joined with cervical intraepithelial neoplasia grade 2 or worse (CIN2+). p16/Ki67 immunohistochemistry gave an interpretable result in 100% of the cases. The use of dual stain significantly increased the agreement between pathologists, which reached 100%. Concordance between dual stain and E6/E7 mRNA test was 89%. In our series, both CISH and p16INK4a/Ki67 dual stain demonstrated high grade of performances. In particular, CISH would help to distinguish episomal from integrated HPV, in order to allow conclusions regarding the prognosis of the lesion, while p16INK4a/Ki67 dual stain approach would confer a high level of standardization to the diagnostic procedure. PMID:24369532

  16. A novel HPV 16 L1-based chimeric virus-like particle containing E6 and E7 seroreactive epitopes permits highly specific detection of antibodies in patients with CIN 1 and HPV-16 infection

    PubMed Central

    2011-01-01

    Background The presence of IgG antibodies to HPV-16 L1-virus like particles (VLPs) in serum has been reported as a result of persistent exposure to the virus and as a marker of disease progression. However, detection of VLP-specific antibodies in sera does not always indicate a malignant lesion as positive results may also be due to a nonmalignant viral infection. Furthermore, malignant lesions are associated with an increased antibody titer for E6 and E7 proteins. The aim of this study was to develop an ELISA using a novel chimeric virus-like particle (cVLP) encoding an L1 protein fused with a string of HPV-16 E6 and E7 seroreactive epitopes to its C-terminus to be used for detection of HPV-16 specific antibodies in patients with cervical intraepithelial lesion grade 1 (CIN 1). Results The sera of 30 patients with CIN 1 who also tested positive for HPV-16 DNA and of 30 age-matched normal donors negative for HPV infection were tested for the presence of IgG antibodies specific for either VLP-L1 (HPV-16 L1), gVLP (derived from Gardasil), or cVLP by ELISA. The cVLP-reactive sera yielded two distinct groups of results: (H) reactivity levels that presented very strong cVLP-specific titers, and (L) reactivity levels with significantly lower titers similar to those obtained with VLP-L1 and gVLP antigens. Additionally, the sera that presented the higher cVLP titers closely matched those that had significantly stronger reactivity to E6 and E7 epitopes. Interestingly, the samples with the highest titers corresponded to patients with the higher numbers of sexual partners and pregnancies. On the other hand only 4 out of the 12 sera that harbored antibodies with VLP neutralizing ability corresponded to the group with high cVLP antibody titers. Conclusion We report for the first time that chimeric particles containing HPV-16 L1 protein fused with E6 and E7 seroreactive epitopes enable much better detection of IgG antibodies in the sera of CIN 1 patients positive for HPV-16 infection than those obtained with VLPs containing only the HPV-16 L1 protein. We also found that the sera with higher cVLP antibody titers corresponded to patients with more sexual partners and pregnancies, and not always with to those with a high neutralizing activity. This novel assay could help in the development of a tool to evaluate cervical cancer risk. PMID:21306638

  17. Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior

    SciTech Connect

    Chen, W. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Li, F.; Mead, L.; White, H. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Walker, J. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Ingram, D.A. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Roman, A. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States)], E-mail: aroman@iupui.edu

    2007-10-10

    One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

  18. Role of interleukin-2 in superantigen-induced T-cell anergy

    PubMed Central

    Cornwell, W D; Rogers, T J

    1999-01-01

    T-cell anergy is a state of immunological tolerance characterized by unresponsiveness to antigenic stimulation. Previous studies have shown that anergy is induced in T cells following stimulation in the absence of adequate costimulatory signals. These cells fail to respond to stimulation via the T-cell receptor (TCR), and fail to produce normal levels of interleukin-2 (IL-2). We present results here which show that low concentrations of the superantigen staphylococcal enterotoxin A (SEA) in the absence of antigen-presenting cells induced both proliferation and anergy in the A.E7 T-cell clone. Furthermore, under these conditions, the A.E7 clone remained responsive to exogenous IL-2. Fluorescence-activated cellular cytometry analysis revealed unaltered expression of the TCR/CD3 complex in the anergized clone; however, both CD4 and CD25 expression increased after 24 hr of stimulation by SEA under these conditions. Interestingly, a low level of IL-2 production was measured during the induction of anergy. Most strikingly, stimulation of the A.E7 clone by SEA in combination with exogenous IL-2 resulted in a more pronounced state of anergy. These results suggest that the induction of anergy is a process that is essentially independent of the production of IL-2. PMID:10233695

  19. The proto-oncogene Bcl3, induced by Tax, represses Tax-mediated transcription via p300 displacement from the human T-cell leukemia virus type 1 promoter.

    PubMed

    Kim, Young-Mi; Sharma, Neelam; Nyborg, Jennifer K

    2008-12-01

    The etiology of human T-cell leukemia virus type 1 (HTLV-1)-induced adult T-cell leukemia is linked to the expression of the viral oncoprotein Tax. Although the mechanism of retroviral transformation is unknown, Tax interferes with fundamental cellular processes, including proliferation and apoptosis, and these events may directly link Tax to early steps in malignant progression. In this study, we examined the interplay between Tax and the potent proto-oncogene B-cell chronic leukemia protein 3 (Bcl3). Bcl3 is a critical regulator of cell survival and proliferation and is overexpressed in HTLV-1-infected cells. We found that Tax induced Bcl3 expression through stimulation of the NF-kappaB pathway. An intronic NF-kappaB binding site within the Bcl3 gene served as the primary target of Tax-induced NF-kappaB activation. We next considered the consequence of Bcl3 overexpression on Tax function. Interestingly, we found that Bcl3 formed a stable complex with Tax and that this complex potently inhibited Tax-dependent HTLV-1 transcription. Importantly, Bcl3 associated with the HTLV-1 promoter in a Tax-dependent manner and inhibited the binding of the critical cellular coactivator p300. The conserved ankyrin repeat domain of Bcl3 mediated both Tax binding and inhibition of p300 recruitment to the HTLV-1 promoter. Together, these data suggest that Tax-induced Bcl3 overexpression benefits the virus in two important ways. First, Bcl3 may promote cell division and thus clonal proliferation of the virus. Second, Bcl3 may attenuate virion production, facilitating immune evasion. One consequence of this regulatory loop may be Bcl3-induced malignant transformation of the host cell. PMID:18815299

  20. Human T Cell Leukemia Virus Type I Tax-Induced I?B-? Modulates Tax-Dependent and Tax-Independent Gene Expression in T Cells1

    PubMed Central

    Kimura, Ryuichiro; Senba, Masachika; Cutler, Samuel J; Ralph, Stephen J; Xiao, Gutian; Mori, Naoki

    2013-01-01

    Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and various inflammatory disorders including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-?B (NF-?B), cyclic adenosine 3?,5?-monophosphate response element-binding protein, and activator protein 1 (AP-1). Here, we show that NF-?B-binding cofactor inhibitor of NF-?B-? (I?B-?) is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the I?B-? gene, mainly through NF-?B. Microarray analysis of I?B-?-expressing uninfected T cells demonstrated that I?B-? induced the expression of NF-?B. and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3), guanylate-binding protein 1, and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-?B-binding domain of I?B-? were required for Bcl3 induction, and I?B-? synergistically enhanced Tax-induced Bcl3 transactivation in an NF-?B-dependent manner. Interestingly, I?B-? inhibited Tax-induced NF-?B, AP-1 activation, and HTLV-I transcription. Furthermore, I?B-? interacted with Tax in vitro and this interaction was also observed in an HTLV-I-transformed T cell line. These results suggest that I?B-? modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of I?B-? may be of significance in ATL genesis and pathogenesis of HTLV-I-associated diseases. PMID:24027435

  1. Requirement for Estrogen Receptor A in a Mouse Model for Human Papillomavirus-Associated Cervical Cancer

    Microsoft Academic Search

    Sang-Hyuk Chung; Kerri Wiedmeyer; Anny Shai; Kenneth S. Korach; Paul F. Lambert

    2008-01-01

    The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPV), which encode the potent E6 and E7 oncogenes. On prolonged treatment with physiologic levels of exogenous estrogen, K14E7 transgenic mice expressing HPV-16 E7 oncoprotein in their squamous epithelia succumb to uterine cervical cancer. Furthermore, prolonged withdrawal of exogenous estrogen results in complete or partial regression of

  2. The Natural Product Avrainvillamide Binds to the Oncoprotein Nucleophosmin

    E-print Network

    - liferative effects, binds to the nuclear chaperone nucleophosmin, a proposed oncogenic protein of nucleophosmin in a population of HeLa S3 cells leads to increased sensitivity of that population toward

  3. bcl-2 oncoprotein in colorectal hyperplastic polyps, adenomas, and adenocarcinomas

    Microsoft Academic Search

    Silvano Bosari; Laura Moneghini; Daniela Graziani; Arthur K. C Lee; John J Murray; Guido Coggi; Giuseppe Viale

    1995-01-01

    The bcl-2 gene is an oncogene that inhibits programmed cell death (apoptosis). We investigated by immunocytochemistry bcl-2 expression in normal colonic mucosa, hyperplastic polyps, adenomas, and adenocarcinomas of the large bowel. The purpose of the investigation was twofold: to assess the possible role of bcl-2 in colorectal tumorigenesis and to evaluate its clinical significance. The cases studied included 24 hyperplastic

  4. Interaction between the retinoblastoma protein and the oncoprotein MDM2

    Microsoft Academic Search

    Zhi-Xlong Xiao; Jiandong Chen; Arnold J. Levine; Nazanlne Modjtahedi; Jun Xing; William R. Sellers; David M. Livingston

    1995-01-01

    INACTIVATION of tumour-suppressor genes leads to deregulated cell proliferation and is a key factor in human tumorigenesis. Both p53 and retinoblastoma genes are frequently mutated in human cancers1,2, and the simultaneous inactivation of RB andp53 is frequently observed in a variety of naturally occurring human tumours3. Furthermore, three distinct DNA tumour virus groups-papovaviruses, adenoviruses and human papillomaviruses-transform cells by targeting

  5. Human papillomavirus 16 E6/E7-immortalized human gingival keratinocytes with epithelial mesenchymal transition acquire increased expression of cIAP-1, Bclx and p27(Kip1).

    PubMed

    Chamulitrat, Walee; Sattayakhom, Apsorn; Herold-Mende, Christel; Herold-Mended, Christel; Stremmel, Wolfgang

    2009-12-01

    Epithelial mesenchymal transition (EMT) has been implicated in neoplastic invasion and metastasis. We have previously generated six cell lines from human gingival mucosal keratinocytes immortalized by E6/E7 of human papillomavirus type 16. Ldk and NuB1 lines represented EMT phenotype and other four lines represented cobblestone non-EMT phenotype. These cell lines were utilized as model cells to determine whether inhibitors of apoptosis proteins and cell-cycle regulators were molecular players during EMT. EMT cells exhibited increased expression of vimentin, vascular endothelial growth factor (VEGF) receptor1 and the ability to form tubules on Matrigel as well as to grow anchorage independently. We found that EMT cells expressed significantly elevated levels of cIAP-1, Bclx and p27(kip) higher than non-EMT cells. These proteins could therefore be used as intrinsic indicators of EMT of human gingival keratinocytes. PMID:19397698

  6. Polycyclic aromatic hydrocarbons-induced ROS accumulation enhances mutagenic potential of T-antigen from human polyomavirus JC.

    PubMed

    Wilk, Anna; Waligórski, Piotr; Lassak, Adam; Vashistha, Himanshu; Lirette, David; Tate, David; Zea, Arnold H; Koochekpour, Shahriar; Rodriguez, Paulo; Meggs, Leonard G; Estrada, John J; Ochoa, Augusto; Reiss, Krzysztof

    2013-11-01

    Polycyclic aromatic hydrocarbons (PAHs) are the products of incomplete combustion of organic materials, which are present in cigarette smoke, deep-fried food, and in natural crude oil. Since PAH-metabolites form DNA adducts and cause oxidative DNA damage, we asked if these environmental carcinogens could affect transforming potential of the human Polyomavirus JC oncoprotein, T-antigen (JCV T-antigen). We extracted DMSO soluble PAHs from Deepwater Horizon oil spill in the Gulf of Mexico (oil-PAHs), and detected several carcinogenic PAHs. The oil-PAHs were tested in exponentially growing cultures of normal mouse fibroblasts (R508), and in R508 stably expressing JCV T-antigen (R508/T). The oil-PAHs were cytotoxic only at relatively high doses (1:50-1:100 dilution), and at 1:500 dilution the growth and cell survival rates were practically unaffected. This non-toxic dose triggered however, a significant accumulation of reactive oxygen species (ROS), caused oxidative DNA damage and the formation of DNA double strand breaks (DSBs). Although oil-PAHs induced similar levels of DNA damage in R508 and R508/T cells, only T-antigen expressing cells demonstrated inhibition of high fidelity DNA repair by homologous recombination (HRR). In contrast, low-fidelity repair by non-homologous end joining (NHEJ) was unaffected. This potential mutagenic shift between DNA repair mechanisms was accompanied by a significant increase in clonal growth of R508/T cells chronically exposed to low doses of the oil-PAHs. Our results indicate for the first time carcinogenic synergy in which oil-PAHs trigger oxidative DNA damage and JCV T-antigen compromises DNA repair fidelity. PMID:23558788

  7. Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion.

    PubMed Central

    Kireeva, M L; MO, F E; Yang, G P; Lau, L F

    1996-01-01

    cyr61 was first identified as a growth factor-inducible immediate-early gene in mouse fibroblasts. The encoded Cyr61 protein is a secreted, cystein-rich heparin-binding protein that associates with the cell surface and the extracellular matrix, and in these aspects it resembles the Wnt-1 protein and a number of known growth factors. During embryogenesis, cyr61 is expressed most notably in mesenchymal cells that are differentiating into chondrocytes and in the vessel walls of the developing circulatory system. cyr61 is a member of an emerging gene family that encodes growth regulators, including the connective tissue growth factor and an avian proto-oncoprotein, Nov cyr61 also shares sequence similarities with two Drosophila genes, twisted gastrulation and short gastrulation, which interact with decapentaplegic to regulate dorsal-ventral patterning. In this report we describe the purification of the Cyr61 protein in a biologically active form, and we show that purified Cyr61 has the following activities: (i) it promotes the attachment and spreading of endothelial cells in a manner similar to that of fibronectin; (ii) it enhances the effects of basic fibroblast growth factor and platelet-derived growth factor on the rate of DNA synthesis of fibroblasts and vascular endothelial cells, although it has no detectable mitogenic activity by itself; and (iii) it acts as a chemotactic factor for fibroblasts. Taken together, these activities indicate that Cyr61 is likely to function as an extracellular matrix signaling molecule rather than as a classical growth factor and may regulate processes of cell proliferation, migration, adhesion, and differentiation during development. PMID:8657105

  8. The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors.

    PubMed Central

    Cayrol, C; Flemington, E K

    1996-01-01

    While oncoproteins encoded by small DNA tumor viruses and Epstein-Barr virus (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch transactivator Zta was found to inhibit growth by causing cell cycle arrest in G0/G1 in several epithelial tumor cell lines. Expression of Zta results in induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up-regulation of p53 and p27 occurs by post-transcriptional mechanisms while expression of p21 is induced at the RNA level in a p53-dependent manner. Inactivation of pRb by transient overexpression of the human papillomavirus E7 oncoprotein indicates that pRb or pRb-related proteins are key mediators of the growth-inhibitory function of Zta. These findings suggest that EBV plays an active role in redirecting epithelial cell physiology to facilitate the viral replicative program through a Zta-mediated growth arrest function. Images PMID:8654372

  9. Exercise-Induced Urticaria

    MedlinePLUS

    MENU Return to Web version Exercise-induced Urticaria Overview What is exercise-induced urticaria? Exercise-induced urticaria is a condition that causes hives and other allergic symptoms. It can occur during ...

  10. Electrochemical quartz crystal microbalance, voltammetry, spectroelectrochemical, and microscopic studies of adsorption behavior for (7E,7{prime}Z)-diphenyl-7,7{prime}-diapocarotene electrochemical oxidation product

    SciTech Connect

    Gao, G.; Wurm, D.B.; Kim, Y.T.; Kispert, L.D. [Univ. of Alabama, Tuscaloosa, AL (United States)] [Univ. of Alabama, Tuscaloosa, AL (United States)

    1997-03-13

    Polymeric products, which are formed by reaction of the dications of (7E,7{prime}Z)-diphenyl-7,7{prime}-diapocarotene (I) generated by electrochemical oxidation in dichloromethane with the neutral carotenoid, are adsorbed on various electrode surfaces. An apparent average molar mass of 5400 g/(mol electrons) was calculated from simultaneous electrochemical quartz crystal microbalance (EQCM) measurements, and the green, fiber-like structure observed by optical microscopy confirms the formation of polymers. X-ray microanalysis of the surface composed of an uneven, layered structure indicates that electrolyte counter anions PF{sub 6}{sup -} are associated with the deposited material. Cathodic stripping voltammetry indicates that the film thickness ranges from 0.16 to 0.84 {mu}m as the charge increases from 10.0 to 51.1 {mu}C. Cation radicals of I show no adsorption behavior nor do the dications of carotenoids terminally substituted with one cyclohexene ring (V) or containing a triple bond at C15 (IV). Apparently a diphenyl-substituted carotenoid containing only double bonds in the backbone is required to observe this unusual behavior. 57 refs., 12 figs., 1 tab.

  11. Exploiting the MDM2-CK1? Protein-Protein Interface to Develop Novel Biologics That Induce UBL-Kinase-Modification and Inhibit Cell Growth

    PubMed Central

    Huart, Anne-Sophie; MacLaine, Nicola J.; Narayan, Vikram; Hupp, Ted R.

    2012-01-01

    Protein-protein interactions forming dominant signalling events are providing ever-growing platforms for the development of novel Biologic tools for controlling cell growth. Casein Kinase 1 ? (CK1?) forms a genetic and physical interaction with the murine double minute chromosome 2 (MDM2) oncoprotein resulting in degradation of the p53 tumour suppressor. Pharmacological inhibition of CK1 increases p53 protein level and induces cell death, whilst small interfering RNA-mediated depletion of CK1? stabilizes p53 and induces growth arrest. We mapped the dominant protein-protein interface that stabilizes the MDM2 and CK1? complex in order to determine whether a peptide derived from the core CK1?-MDM2 interface form novel Biologics that can be used to probe the contribution of the CK1-MDM2 protein-protein interaction to p53 activation and cell viability. Overlapping peptides derived from CK1? were screened for dominant MDM2 binding sites using (i) ELISA with recombinant MDM2; (ii) cell lysate pull-down towards endogenous MDM2; (iii) MDM2-CK1? complex-based competition ELISA; and (iv) MDM2-mediated ubiquitination. One dominant peptide, peptide 35 was bioactive in all four assays and its transfection induced cell death/growth arrest in a p53-independent manner. Ectopic expression of flag-tagged peptide 35 induced a novel ubiquitin and NEDD8 modification of CK1?, providing one of the first examples whereby NEDDylation of a protein kinase can be induced. These data identify an MDM2 binding motif in CK1? which when isolated as a small peptide can (i) function as a dominant negative inhibitor of the CK1?-MDM2 interface, (ii) be used as a tool to study NEDDylation of CK1?, and (iii) reduce cell growth. Further, this approach provides a technological blueprint, complementing siRNA and chemical biology approaches, by exploiting protein-protein interactions in order to develop Biologics to manipulate novel types of signalling pathways such as cross-talk between NEDDylation, protein kinase signalling, and cell survival. PMID:22916255

  12. Allosteric regulation of MDM2 protein 

    E-print Network

    Wawrzynów, Bartosz

    2010-01-01

    The diverse functions of the MDM2 oncoprotein in growth control and tumourigenesis are managed through coordinated regulation of its discrete domains induced by both extrinsic and intrinsic stimuli. A picture of MDM2 ...

  13. Regulation of cellular miRNA expression by human papillomaviruses

    PubMed Central

    Zheng, Zhi-Ming; Wang, Xiaohong

    2011-01-01

    High-risk HPV infection leads to aberrant expression of cellular oncogenic and tumor suppressive miRNAs. A large number of these miRNA genes are downstream targets of the transcription factors c-Myc, p53, and E2F and their expression can therefore be modulated by oncogenic HPV E6 and E7. Cervical cancer represents an unique tumor model for understanding how viral E6 and E7 oncoproteins deregulate the expression of the miR-15/16 cluster, miR-17-92 family, miR-21, miR-23b, miR-34a, and miR-106b/93/25 cluster via the E6–p53 and E7–pRb pathways. Moreover, miRNAs may influence the expression of papillomavirus genes in a differentiation-dependent manner by targeting viral RNA transcripts. Cellular miRNAs affecting HPV DNA replication are of great interest and will be a future focus. We are entering an era focusing on miRNA and noncoding RNA, and the study of HPV and host miRNA interactions will continue to shed more light on our understanding of the HPV life cycle and the mechanistic underpinnings of HPV-induced oncogenesis. PMID:21616186

  14. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

    PubMed Central

    Marzec, Michal; Zhang, Qian; Goradia, Ami; Raghunath, Puthiyaveettil N.; Liu, Xiaobin; Paessler, Michele; Wang, Hong Yi; Wysocka, Maria; Cheng, Mangeng; Ruggeri, Bruce A.; Wasik, Mariusz A.

    2008-01-01

    The mechanisms of malignant cell transformation caused by the oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of NPM/ALK on cell survival and proliferation. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells strongly express the immunosuppressive cell-surface protein CD274 (PD-L1, B7-H1), as determined on the mRNA and protein level. The CD274 expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as demonstrated by inhibition of the NPM/ALK function in ALK+TCL cells by the small molecule ALK inhibitor CEP-14083 and by documenting CD274 expression in IL-3-depleted BaF3 cells transfected with the wild-type NPM/ALK, but not the kinase-inactive NPM/ALK K210R mutant or empty vector alone. NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3. STAT3 binds to the CD274 gene promoter in vitro and in vivo, as shown in the gel electromobility shift and chromatin immunoprecipitation assays, and is required for the PD-L1 gene expression, as demonstrated by siRNA-mediated STAT3 depletion. These findings identify an additional cell-transforming property of NPM/ALK and describe a direct link between an oncoprotein and an immunosuppressive cell-surface protein. These results also provide an additional rationale to therapeutically target NPM/ALK and STAT3 in ALK+TCL. Finally, they suggest that future immunotherapeutic protocols for this type of lymphoma may need to include the inhibition of NPM/ALK and STAT3 to achieve optimal clinical efficacy. PMID:19088198

  15. Polymeric nanoparticles for co-delivery of synthetic long peptide antigen and poly IC as therapeutic cancer vaccine formulation.

    PubMed

    Rahimian, Sima; Fransen, Marieke F; Kleinovink, Jan Willem; Christensen, Jonatan Riis; Amidi, Maryam; Hennink, Wim E; Ossendorp, Ferry

    2015-04-10

    The aim of the current study was to develop a cancer vaccine formulation for treatment of human papillomavirus (HPV)-induced malignancies. Synthetic long peptides (SLPs) derived from HPV16 E6 and E7 oncoproteins have been used for therapeutic vaccination in clinical trials with promising results. In preclinical and clinical studies adjuvants based on mineral oils (such as incomplete Freund's adjuvant (IFA) and Montanide) are used to create a sustained release depot at the injection site. While the depot effect of mineral oils is important for induction of robust immune responses, their administration is accompanied with severe adverse and long lasting side effects. In order to develop an alternative for IFA family of adjuvants, polymeric nanoparticles (NPs) based on hydrophilic polyester (poly(d,l lactic-co-hydroxymethyl glycolic acid) (pLHMGA)) were prepared. These NPs were loaded with a synthetic long peptide (SLP) derived from HPV16 E7 oncoprotein and a toll like receptor 3 (TLR3) ligand (poly IC) by double emulsion solvent evaporation technique. The therapeutic efficacy of the nanoparticulate formulations was compared to that of HPV SLP+poly IC formulated in IFA. Encapsulation of HPV SLP antigen in NPs substantially enhanced the population of HPV-specific CD8+ T cells when combined with poly IC either co-encapsulated with the antigen or in its soluble form. The therapeutic efficacy of NPs containing poly IC in tumor eradication was equivalent to that of the IFA formulation. Importantly, administration of pLHMGA nanoparticles was not associated with adverse effects and therefore these biodegradable nanoparticles are excellent substitutes for IFA in cancer vaccines. PMID:25660830

  16. Denture-Induced Stomatitis

    MedlinePLUS

    Denture-Induced Stomatitis What Is It? Symptoms Diagnosis Expected Duration Prevention Treatment When To Call a Professional Prognosis What Is It? Denture-induced stomatitis is usually seen in people who ...

  17. Laser-Induced Thermotherapy

    Microsoft Academic Search

    Birger Mensel; Christiane Weigel; Norbert Hosten

    Laser-induced interstitial thermotherapy is a method for controlled tissue destruction. Cells compounds are destroyed in situ by hyperthermia. Laser-induced thermotherapy (LITT) is able to induce a circumscript necrosis in targeted tissue while maximally surrounding tissue. The first patients were treated 20 years ago and pos sible gains in therapy of oncologic patients were quickly recognized. LITT has gained broad clinical

  18. Cavitation-resistant inducer

    DOEpatents

    Dunn, C.; Subbaraman, M.R.

    1989-06-13

    An improvement in an inducer for a pump is disclosed wherein the inducer includes a hub, a plurality of radially extending substantially helical blades and a wall member extending about and encompassing an outer periphery of the blades. The improvement comprises forming adjacent pairs of blades and the hub to provide a substantially rectangular cross-sectional flow area which cross-sectional flow area decreases from the inlet end of the inducer to a discharge end of the inducer, resulting in increased inducer efficiency improved suction performance, reduced susceptibility to cavitation, reduced susceptibility to hub separation and reduced fabrication costs. 11 figs.

  19. Cavitation-resistant inducer

    DOEpatents

    Dunn, Charlton (Calabasas, CA); Subbaraman, Maria R. (Canoga Park, CA)

    1989-01-01

    An improvement in an inducer for a pump wherein the inducer includes a hub, a plurality of radially extending substantially helical blades and a wall member extending about and encompassing an outer periphery of the blades. The improvement comprises forming adjacent pairs of blades and the hub to provide a substantially rectangular cross-sectional flow area which cross-sectional flow area decreases from the inlet end of the inducer to a discharge end of the inducer, resulting in increased inducer efficiency improved suction performance, reduced susceptibility to cavitation, reduced susceptibility to hub separation and reduced fabrication costs.

  20. Solution 1H nuclear magnetic resonance determination of the distal pocket structure of cyanomet complexes of genetically engineered sperm whale myoglobin His64 (E7)-->Val, Thr67 (E10)-->Arg. The role of distal hydrogen bonding by Arg67 (E10) in modulating ligand tilt.

    PubMed Central

    Qin, J; La Mar, G N; Cutruzzolá, F; Allocatelli, C T; Brancaccio, A; Brunori, M

    1993-01-01

    Sequence-specific 2D methodology has been used to assign the 1H NMR signals for all active site residues in the paramagnetic cyano-met complexes of sperm whale synthetic double mutant His64[E7]-->Val/Thr67[E10]-->Arg (VR-met-MbCN) and triple mutant His64[E7]-->Val/Thr67[E10]-->Arg/Arg45[CD3]-->Asn (VRN-metMbCN). The resulting dipolar shifts for noncoordinated proximal side residues were used to quantitatively determine the orientation of the paramagnetic susceptibility tensor in the molecular framework for the two mutants, which were found indistinguishable but distinct from those of both wild-type and the His64[E7]-->Val single point mutant (V-metMbCN). The observed dipolar shifts for the E helix backbone protons and Phe43[CD1], together with steady-state nuclear Overhauser effect between the E helix and the heme, were analyzed to show that both the E helix and Phe43[CD1] move slightly closer to the iron to minimize the vacancy resulting from the His64[E7]-->Val substitution, as found in V-metMbCN (Rajarathnam, K., J. Qin, G.N. LaMar, M. L. Chiu, and S. G. Sligar. 1993. Biochemistry. 32:5670-5680). The dipolar shifts of the mutated Val64[E7] and Arg67[E10] allow the determination of their orientations relative to the heme, and the latter residue is shown to insert into the pocket and provide a hydrogen bond to the coordinated ligand, as found in the naturally occurring ValE7/ArgE10 genetic variant, Aplysia limacina Mb. The oxy-complex of both A. limacina Mb and VR-Mb, VRN-Mb have been proposed to be stabilized by this hydrogen bonding interaction (Travaglini Allocatelli, C. et al. 1993. Biochemistry. 32:6041-6049). The magnitude of the tilt of the major magnetic axes from the heme normal in VR-metMbCN and VRN-metMbCN, which is related to the tilt of the ligand, is the same as in wild-type or V-metMbCN, but the direction of tilt is altered from that in V-metMbCN. It is concluded that the change in the direction of the ligand tilt in both the double and triple mutants, as compared to WT metMbCN and V-metMbCN single mutant, is due to the attractive hydrogen-bonding between ArgE10 and the bound cyanide. PMID:8298042

  1. Exercise-induced anaphylaxis

    Microsoft Academic Search

    Mariana C. Castells; Richard F. Horan; Albert L. Sheffer

    2003-01-01

    Exercise-induced anaphylaxis has been recognized with increasing frequency since its original description in 1980. Recent\\u000a studies suggest food-induced reactions may occur frequently in this syndrome, which is a mast cell-dependent phenomenon. In\\u000a this article, the clinical manifestations of exercise-induced anaphylaxis are reviewed, and food related factors contributing\\u000a to the disorder are considered.

  2. 12/20/09 5:38 PMAbstract Print View Page 1 of 2http://www.abstractsonline.com/Plan/AbstractPrintView.aspx?mID=2...48b8-a9d6-0cf5ddbded14&cKey=257426df-499b-4f28-9e7c-ca8985039150

    E-print Network

    Shenoy, Krishna V.

    .abstractsonline.com/Plan/AbstractPrintView.aspx?mID=2...48b8-a9d6-0cf5ddbded14&cKey=257426df-499b-4f28-9e7c-ca8985039150 Print this Page Presentation Abstract Program#/Poster#: 463.9/CC60 Title: The tuning of plan activity in premotor / motor cortex is best captured by intrinsic parameters derived from the movement-period population response Location: South Hall

  3. Exercise-Induced Asthma

    MedlinePLUS

    ... any changes with your child's breathing problems. Recommended Activities for Kids With EIA Exercise is a great idea for ... With Exercise-Induced Asthma For the most part, kids with exercise-induced ... activity, in addition to stretching or flexibility exercises.) Take ...

  4. Induced mutations in rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Induced mutations have a long history in both applied and basic aspects of rice research. During the past fifty years, over 500 rice varieties have been developed worldwide, either directly from induced mutants or as a result of crossing such mutants with other breeding lines. More recently, the gen...

  5. Quinine-Induced Thrombocytopenia

    PubMed Central

    Lefkowitz, Jack M.; Shapiro, Marla

    1986-01-01

    Severe drug-induced thrombocytopenia (DIT) is a relatively rare, but potentially lethal, complication of pharmacological therapy. Quinine, a drug commonly used for the treatment of leg cramps, is one of the most frequent causes of DIT. This article reports a case of quinine-induced thrombocytopenia (QIT) and reviews the literature on the subject. PMID:21267300

  6. Movie induced tourism

    Microsoft Academic Search

    Roger Riley; Dwayne Baker; Carlton S. Van Doren

    1998-01-01

    Movies provide the objects and subjects for the gaze of many people, and for some people, movies induce them to travel to the locations where they were filmed. The data gathered at 12 US locations supports earlier anecdotal accounts of movie-induced tourism. This paper extends from earlier studies by suggesting a variety of reasons for this type of gaze and

  7. Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation.

    PubMed Central

    Hirai, H; Suzuki, T; Fujisawa, J; Inoue, J; Yoshida, M

    1994-01-01

    Human T-cell leukemia virus type I causes adult T-cell leukemia and tropical spastic paraparesis, and its regulator protein Tax has been implicated in the pathogenic activity of human T-cell leukemia virus type I. Tax activates transcription of viral and cellular genes through specific enhancers: the 21-bp enhancer of human T-cell leukemia virus type I, the nuclear factor kappa B (NF-kappa B)-binding site of the interleukin 2 receptor alpha gene, and the serum-responsive element of c-fos. Tax binds to enhancer-binding proteins including cAMP-responsive element-binding protein, cAMP-responsive element modulator, transcription factor NF-kappa B p50 and p67SRF, and associates with each enhancer DNA indirectly. In addition to this mechanism, we report here that Tax binds to inhibitory factor kappa B gamma (I-kappa B) gamma, which forms a complex with NF-kappa B protein heterodimer p50-p65 or homodimer p50-p50 and retains them in the cytoplasm. Tax binding to I-kappa B gamma induces nuclear translocation of NF-kappa B p65. In association with this nuclear translocation of p65, transcription directed by the kappa B enhancer is strongly activated. Tax binds to the ankyrin motifs of I-kappa B gamma, suggesting its possible interaction with many other proteins carrying ankyrin motifs contributing to various regulatory processes. This is a different mechanism of transcriptional activation by the oncoprotein Tax and seems to be independent from the trans-activation through indirect binding to enhancer DNAs. Images PMID:8170951

  8. Induced pluripotency with endogenous and inducible genes

    SciTech Connect

    Duinsbergen, Dirk [Department of Molecular Cell Biology and Regenerative Medicine Program, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden (Netherlands); Eriksson, Malin [Department of Cell and Molecular Biology, Karolinska Institute, Box 285, S171 77, Stockholm (Sweden); Hoen, Peter A.C. 't [Center for Human and Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden (Netherlands); Frisen, Jonas [Department of Cell and Molecular Biology, Karolinska Institute, Box 285, S171 77, Stockholm (Sweden); Mikkers, Harald [Department of Molecular Cell Biology and Regenerative Medicine Program, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden (Netherlands)], E-mail: h.mikkers@lumc.nl

    2008-10-15

    The recent discovery that two partly overlapping sets of four genes induce nuclear reprogramming of mouse and even human cells has opened up new possibilities for cell replacement therapies. Although the combination of genes that induce pluripotency differs to some extent, Oct4 and Sox2 appear to be a prerequisite. The introduction of four genes, several of which been linked with cancer, using retroviral approaches is however unlikely to be suitable for future clinical applications. Towards developing a safer reprogramming protocol, we investigated whether cell types that express one of the most critical reprogramming genes endogenously are predisposed to reprogramming. We show here that three of the original four pluripotency transcription factors (Oct4, Klf4 and c-Myc or MYCER{sup TAM}) induced reprogramming of mouse neural stem (NS) cells exploiting endogenous SoxB1 protein levels in these cells. The reprogrammed neural stem cells differentiated into cells of each germ layer in vitro and in vivo, and contributed to mouse development in vivo. Thus a combinatorial approach taking advantage of endogenously expressed genes and inducible transgenes may contribute to the development of improved reprogramming protocols.

  9. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo

    Microsoft Academic Search

    Akira Inoue; Markus G. Seidel; Wenshu Wu; Shintaro Kamizono; Adolfo A. Ferrando; Roderick T. Bronson; Hiromi Iwasaki; Koichi Akashi; Akira Morimoto; Johann K. Hitzler; Tamara I. Pestina; Carl W. Jackson; Ryuhei Tanaka; Miriam J. Chong; Peter J. McKinnon; Takeshi Inukai; Gerard C. Grosveld; A. Thomas Look

    2002-01-01

    We show here that a zinc finger transcriptional repressor, Slug, which is aberrantly upregulated by the E2A-HLF oncoprotein in pro-B cell acute leukemia, functions as an antiapoptotic factor in normal hematopoietic progenitor cells. Slug?\\/? mice were much more radiosensitive than wild-type mice, dying earlier and showing accentuated decreases in peripheral blood cell counts, as well as abundant microhemorrhages and widely

  10. Drug-induced phospholipidosis.

    PubMed

    Anderson, Nora; Borlak, Jürgen

    2006-10-01

    Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes. Despite significant advances in the understanding of drug-altered lipid metabolism, the relationship between impaired phospholipid metabolism and drug-induced toxicity remains enigmatic. Here we review molecular features of inheritable lysosomal storage disorders as a molecular mimicry of drug-induced phospholipidosis for an improved understanding of adverse drug reaction. PMID:16979167

  11. Space Station Induced Monitoring

    NASA Technical Reports Server (NTRS)

    Spann, James F. (editor); Torr, Marsha R. (editor)

    1988-01-01

    This report contains the results of a conference convened May 10-11, 1988, to review plans for monitoring the Space Station induced environment, to recommend primary components of an induced environment monitoring package, and to make recommendations pertaining to suggested modifications of the Space Station External Contamination Control Requirements Document JSC 30426. The contents of this report are divided as Follows: Monitoring Induced Environment - Space Station Work Packages Requirements, Neutral Environment, Photon Emission Environment, Particulate Environment, Surface Deposition/Contamination; and Contamination Control Requirements.

  12. Mania Induced by Opipramol

    PubMed Central

    Firoz, Kazhungil; Khaleel, Asfia; Rajmohan, V; Kumar, Manoj; Raghuram, TM

    2015-01-01

    Antidepressants have propensity to induce manic switch in patients with bipolar disorder. Opipramol is an atypical anxiolytic and antidepressant drug which predominantly acts on sigma receptors. Although structurally resembles tricyclic antidepressant imipramine it does not have inhibitory action on the reuptake of norepinephrine/serotonin and hence it is not presumed to cause manic switch in bipolar depression. Here, we describe a case of mania induced by opipramol, in a patient with bipolar affective disorder who was treated for moderate depressive episode with lithium and opipramol and we discuss neurochemical hypothesis of opipramol-induced mania. PMID:25722522

  13. Induced multiferroics: and materials

    E-print Network

    Natelson, Douglas

    Induced multiferroics: symmetry, coupling, and materials Art Ramirez, LGS (formerly Lucent, February 2, 2009 Outline Overview of magneto-electric multiferroics Role of geometrical frustration per function reduction) and performance (speed, power) and reliability values to the applications

  14. Drug-induced hepatitis

    MedlinePLUS

    ... induced hepatitis. Painkillers and fever reducers that contain acetaminophen are a common cause of liver inflammation. These ... problem. However, if you took high doses of acetaminophen , treatment should be started as soon as possible ...

  15. Olanzapine-induced vasculitis

    Microsoft Academic Search

    Mahesh K. Duggal; Amritpal Singh; Arunabh; James D. Lolis; Howard J. Guzik

    2005-01-01

    Introduction:Elderly patients are particularly vulnerable to adverse drug reactions as a result of polypharmacy and metabolic changes associated with aging. We present a case of leukocytoclastic vasculitis induced by olanzapine, a medication commonly used in elderly patients.

  16. Vitiligo, drug induced (image)

    MedlinePLUS

    ... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat (macular) and depigmented, but maintains ...

  17. Thrombocytopenia - drug induced

    MedlinePLUS

    ... and a seizure medication called valproic acid may lead to this problem. Other medicines that cause drug-induced thrombocytopenia include: Furosemide Gold, used to treat arthritis Nonsteroidal anti-inflammatory drugs ( ...

  18. Gasoline-induced mucositis

    SciTech Connect

    Hoffman, D.L.; Swanson, B.Z. Jr.; Lutins, N.D.

    1980-02-01

    Gasoline-induced mucositis may become more common because of fuel shortages or increased fuel cost. Dentists should, therefore, consider this oral irritant in the differential diagnosis of oral lesions.

  19. Drug-induced phospholipidosis

    Microsoft Academic Search

    Nora Anderson; Jürgen Borlak

    2006-01-01

    Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes. Despite significant advances in the understanding of drug-altered lipid metabolism, the relationship between impaired phospholipid metabolism and drug-induced toxicity remains enigmatic. Here we review molecular features of inheritable

  20. Induced polarization response of microbial induced sulfideprecipitation

    SciTech Connect

    Ntarlagiannis, Dimitrios; Williams, Kenneth Hurst; Slater, Lee; Hubbard, Susan

    2004-06-04

    A laboratory scale experiment was conducted to examine the use of induced polarization and electrical conductivity to monitor microbial induced sulfide precipitation under anaerobic conditions in sand filled columns. Three columns were fabricated; one for electrical measurements, one for geochemical sampling and a third non-inoculated column was used as a control. A continual upward flow of nutrients and metals in solution was established in each column. Desulfovibrio vulgaris microbes were injected into the middle of the geochemical and electrical columns. Iron and zinc sulfides precipitated along a microbial action front as a result of sulfate reduction due by Desulfovibrio vulgaris. The precipitation front initially developed near the microbial injection location, and subsequently migrated towards the nutrient inlet, as a result of chemotaxis by Desulfovibrio vulgaris. Sampling during and subsequent to the experiment revealed spatiotemporal changes in the biogeochemical measurements associated with microbial sulfate reduction. Conductivity measurements were insensitive to all biogeochemical changes occurred within the column. Changes in the IP response (of up to 14 mrad)were observed to coincide in place and in time with the active microbe respiration/sulfide precipitation front as determined from geochemical sampling. The IP response is correlated with the lactate concentration gradient, an indirect measurement of microbial metabolism, suggesting the potential of IP as a method for monitoring microbial respiration/activity. Post experimental destructive sample analysis and SEM imaging verified the geochemical results and supported our hypothesis that microbe induced sulfide precipitation is directly detectable using electrical methods. Although the processes not fully understood, the IP response appears to be sensitive to this anaerobic microbial precipitation, suggesting a possible novel application for the IP method.

  1. Drug-induced panniculitides.

    PubMed

    Borroni, G; Torti, S; D'Ospina, R M; Pezzini, C

    2014-04-01

    A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their possible etiologic role in inducing among other side effects, also panniculitides. PMID:24819647

  2. Werner syndrome protein limits MYC-induced cellular senescence

    PubMed Central

    Grandori, Carla; Wu, Kou-Juey; Fernandez, Paula; Ngouenet, Celine; Grim, Jonathan; Clurman, Bruce E.; Moser, Michael J.; Oshima, Junko; Russell, David W.; Swisshelm, Karen; Frank, Scott; Amati, Bruno; Dalla-Favera, Riccardo; Monnat, Raymond J.

    2003-01-01

    The MYC oncoprotein is a transcription factor that coordinates cell growth and division. MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli. Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene, WRN, which encodes a conserved RecQ helicase. Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence. The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed by hTERT expression. We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence. PMID:12842909

  3. Drug-induced esophagitis.

    PubMed

    Zografos, G N; Georgiadou, D; Thomas, D; Kaltsas, G; Digalakis, M

    2009-01-01

    Drug-induced esophagitis is being recognized increasingly in the past few years. Since 1970 more than 650 cases have been reported worldwide caused by 30 or more medications. We have reviewed these cases with a view to classifying this disease based on underlying pathological mechanism. Drug-induced esophageal injury tends to occur at the anatomical site of narrowing, with the middle third behind the left atrium predominating (75.6%). The disease is broadly classified into two groups. The first group being transient and self-limiting as exemplified by the tetracycline group induced injury (65.8%). The second is the persistent esophagitis group, often with stricture, with two distinct entities: (i) patients on nonsteroidal anti-inflammatory agents whose injury is aggravated by gastroesophageal reflux (21.8%) (reflux aggravated); and (ii) patients with potasium chloride and quinidine sulphate induced injury (12.4%) (persistent drug injury). Severe esophageal injury has been reported in some women taking biphosphonates as treatment for postmenopausal osteoporosis. Endoscopic findings in such patients with esophageal injury generally suggested a chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall. Most cases of medication-induced esophageal injury heal without intervention within a few days. Thus, the most important aspect of therapy is to make the correct diagnosis and then to avoid reinjury with the drug. When possible, potentially caustic oral medications should be discontinued. PMID:19392845

  4. [Exercise-induced anaphylaxis].

    PubMed

    Wylon, K; Hompes, S; Worm, M

    2013-02-01

    Exercise-induced anaphylaxis is a mast cell dependent reaction, which is induced by allergen exposure in combination with physical activity. Typically, the reaction occurs within 2 hours after allergen exposure followed by physical activity. Not only food allergens but all kinds of allergens including drugs can induce this form of anaphylaxis. The clinical symptoms of exercise-induced anaphylaxis are the same as in any other type of anaphylaxis. Thus not only the skin and mucosa but also other organ systems like the lungs, cardiovascular system and gastrointestinal tract can be affected. The diagnostic work up should cover a detailed clinical history including the assessment of symptoms and possible trigger factors including suspected allergens. Besides classical allergy diagnostics like skin prick tests and specific IgE determination, tryptase should be measured for the differential diagnosis to exclude mast cell dependent diseases. The diagnosis of exercise-induced anaphylaxis is made by the means of a double-blind placebo-controlled provocation test. Both, a sufficient amount of allergen and of physical activity must be achieved for a valid test. After the diagnosis is made, patients should be extensively counseled and provided with an emergency kit including an epinephrine auto injector. PMID:23385620

  5. Pterostilbene suppresses benzo[a]pyrene-induced airway remodeling.

    PubMed

    Kuo, Po-Lin; Hsu, Ya-Ling; Tsai, Ming-Ju; Huang, Ming-Shyan

    2011-07-27

    This study has two novel findings: it is not only the first to demonstrate inflammatory cytokines, which are produced by the bronchial epithelium after exposure to benzo[a]pyrene (BaP) and contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) proliferation and migration, but also the first to reveal that pterostilbene, a constituent of grapes and berries, reverses BaP-mediated airway remodeling. Human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE) were treated with BaP, and then the condition medium (CM) was harvested, which was then added to BSMC. Cultures of BSMC with BaP-BEAS-2B-CM and -HBE-CM increased BSMC proliferation and migration, which are major features in asthma remodeling. Exposure of BEAS-2B and HBE to BaP caused epithelial cells to produce inflammatory cytokines IL-8, which subsequently induced BSMC proliferation and migration. Moreover, pterostilbene is more potent than resveratrol in suppressing BaP-mediated airway remodeling. This study suggests that pterostilbene is capable of preventing BaP-associated asthma. PMID:21675704

  6. Stimulant-induced trichotillomania.

    PubMed

    Hamalian, Gareen; Citrome, Leslie

    2010-01-01

    A prior report described the presentation of cocaine-induced trichotillomania, which resolved with the cessation of cocaine use. Here the authors describe the case of stimulant-induced trichotillomania that resolved with the discontinuation of stimulants and initiation of olanzapine. To the authors' knowledge this is the first reported adult case of stimulant-induced trichotillomania. The case is of a patient with a previous diagnosis of attention deficit hyperactivity disorder whose symptoms of trichotillomania coincide with abuse of amphetamine and with the resolution of symptoms in the absence of amphetamine use. Given the increase in exposure of prescription amphetamines among adults, further study into the association between stimulants and adverse events such as trichotillomania is needed. PMID:20391272

  7. Irradiation-Induced Nanostructures

    SciTech Connect

    Birtcher, R.C.; Ewing, R.C.; Matzke, Hj.; Meldrum, A.; Newcomer, P.P.; Wang, L.M.; Wang, S.X.; Weber, W.J.

    1999-08-09

    This paper summarizes the results of the studies of the irradiation-induced formation of nanostructures, where the injected interstitials from the source of irradiation are not major components of the nanophase. This phenomena has been observed by in situ transmission electron microscopy (TEM) in a number of intermetallic compounds and ceramics during high-energy electron or ion irradiations when the ions completely penetrate through the specimen. Beginning with single crystals, electron or ion irradiation in a certain temperature range may result in nanostructures composed of amorphous domains and nanocrystals with either the original composition and crystal structure or new nanophases formed by decomposition of the target material. The phenomenon has also been observed in natural materials which have suffered irradiation from the decay of constituent radioactive elements and in nuclear reactor fuels which have been irradiated by fission neutrons and other fission products. The mechanisms involved in the process of this nanophase formation are discussed in terms of the evolution of displacement cascades, radiation-induced defect accumulation, radiation-induced segregation and phase decomposition, as well as the competition between irradiation-induced amorphization and recrystallization.

  8. Capecitabine-induced pancreatitis.

    PubMed

    Yucel, Hanifi; Warmerdam, Laurence V

    2010-06-01

    Capecitabine is an oral pro-drug of fluorouracil, which is a commonly used cytotoxic drug in the treatment of colorectal carcinoma. Many adverse effects are known to occur with capecitabine including diarrhea, palmar-planter erythrodysesthesia and nausea. We report a case of capecitabine-induced pancreatitis, also occurring with re-challenge. PMID:19700478

  9. Neuroleptic-induced hyperprolactinemia

    Microsoft Academic Search

    Ruth A. Dickson; William M. Glazer

    1999-01-01

    Neuroleptic-induced hyperprolactinemia (NIHP) has been a `cost' of traditional antipsychotic therapy. Because all of the traditional neuroleptics are capable of elevating serum prolactin, clinicians have had to accept the implications of NIHP along with the antipsychotic's efficacy. Accordingly, the clinical consequences of NIHP have received limited attention. With the introduction of some of the new, more highly selective mesolimbic and

  10. Pregnancy-Induced Hypertension

    MedlinePLUS

    ... best treatment for me? Will I need bed rest? Will it be necessary to induce labor? Will I need a C-section? What are the risks of early delivery for my baby? Source NHBPEP Report on High Blood Pressure in Pregnancy: A Summary for Family Physicians by MA Zamorski, ...

  11. Friction induced rail vibrations

    NASA Astrophysics Data System (ADS)

    Kralov, Ivan; Sinapov, Petko; Nedelchev, Krasimir; Ignatov, Ignat

    2012-11-01

    A model of rail, considered as multiple supported beam, subjected on friction induced vibration is studied in this work using FEM. The model is presented as continuous system and the mass and elastic properties of a real object are taken into account. The friction forces are nonlinear functions of the relative velocity during slipping. The problem is solved using Matlab Simulink.

  12. Signaling in Induced Resistance

    Microsoft Academic Search

    John P. Carr; Mathew G. Lewsey; Peter Palukaitis

    2010-01-01

    Induced mechanisms are by definition imperceptible or less active in uninfected, unstressed, or untreated plants, but can be activated by pathogen infection, stress, or chemical treatment to inhibit the replication and movement of virus in the host. In contrast, defenses that are pre-existing or serve to limit virus propagation and spread in otherwise susceptible hosts are considered to be “basal”

  13. Laser induced copper plating

    Microsoft Academic Search

    A. K. Al-Sufi; H. J. Eichler; J. Salk; H. J. Riedel

    1983-01-01

    Argon laser induced plating of copper spots and lines from copper sulfate solutions on glass and phenolic resin paper has been investigated. The substrates had to be precoated with an evaporated copper film. The highest plating rates have been obtained with a small film thickness of 25 nm. Spots with a thickness up to 30 ?m were plated.

  14. DRUG INDUCED CHOLESTASIS

    PubMed Central

    Padda, Manmeet S.; Sanchez, Mayra; Akhtar, Abbasi J.; Boyer, James L.

    2011-01-01

    Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug induced cholestasis. This review summarizes their variable clinical presentations, examines the, role of transport proteins in hepatic drug clearance and toxicity and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management. PMID:21480339

  15. Drug-induced myopathies.

    PubMed

    Le Quintrec, J S; Le Quintrec, J L

    1991-04-01

    Myopathies are not an unusual complication of drug therapy. The major symptoms in drug-induced myopathies are proximal muscle weakness, increased muscle enzyme levels, electromyographic changes and histological lesions. Some drug-induced myopathies are associated with neuropathy. Drug-induced myopathies can be classified according to the presence or absence of muscular pain and associated neuropathy. Among painless myopathies, we can distinguish myopathies without neuropathy (corticosteroids), myopathies with neuropathy (colchicine, chloroquine and hydroxychloroquine) and myasthenic syndromes (D-penicillamine, antibiotics, beta-blockers). Among painful myopathies, the classification is similar: painful myopathies may or may not be associated with neuropathies. Painful myopathies include polymyositis (D-penicillamine, cimetidine, zidovudine) and other myopathies without polymyositis (clofibrate, statines, cyclosporin). Among the painful neuromyopathies, eosinophilia-myalgia syndrome is a recently described disorder associated with the use of L-tryptophan. Combinations of drugs (for example, a fibrate and a statine or cyclosporin and colchicine) can induce severe myopathies. If such drugs are used together a vigorous surveillance to detect any sign of myopathy is warranted. Instead of classifying drug-induced myopathies according to clinical features, a histological classification can be proposed. Many drugs can induce vacuolar myopathy (colchicine, chloroquine, amiodarone, cyclosporin, drugs causing hypokalaemia and lipid-lowering agents), some others cause a mitochondrial myopathy (zidovudine) or a necrotizing myopathy as seen with vincristine. Overall, several criteria for reporting drug-induced myopathy can be recommended: lack of pre-existent muscular symptoms, a free period between the beginning of the treatment and the appearance of symptoms, lack of another cause accounting for the myopathy, and complete or incomplete resolution after withdrawal of the treatment. Rechallenge of the treatment is not advisable because of the risk of a serious relapse. The exact mechanisms by which drugs cause myopathies are unknown. Some cases may be due to metabolic changes, whereas others may be immune mediated. Nevertheless, the aspect these conditions have in common is the regression of the myopathy with the discontinuation of the drug. PMID:2070426

  16. Malathion-induced granulosa cell apoptosis in caprine antral follicles: an ultrastructural and flow cytometric analysis.

    PubMed

    Bhardwaj, Jitender K; Saraf, Priyanka

    2014-12-01

    Organophosphate pesticides (OPs) like malathion interfere with normal ovarian function resulting in an increased incidence of atresia and granulosa cell apoptosis that plays a consequential role in the loss of ovarian follicles or follicular atresia. The aim of present study was to assess malathion-induced (100 nM) reproductive stress, ultrastructural damage and changes in apoptosis frequency in ovarian granulosa cells of antral follicles. Transmission electron microscopy (TEM) was employed for ultrastructural characterization, oxidative stress was evaluated using thiobarbituric acid reactive substances (TBARS) assay to measure lipid peroxidation, and apoptosis was quantified via flow cytometry. By TEM, apoptosis was identified by the presence of an indented nuclear membrane with blebbing, pyknotic crescent-shaped fragmented nuclei, increased vacuolization, degenerating mitochondria, and lipid droplets. The results indicate a significant increase in malondialdehyde (MDA) level (nmols/g wet tissue) at a 100 nM dose of malathion i.e. 7.57±0.033*, 8.53±0.12*, and 12.87±0.78** at 4, 6, or 8 h, respectively, as compared with controls (6.07±0.033, p<0.01*, p<0.05**) showing a positive correlation between malathion-induced lipid peroxidation and percentage of granulosa cell apoptosis (r=1; p<0.01). The parallel use of these three methods enabled us to determine the role of malathion in inducing apoptosis as a consequence of cytogenetic damage and oxidative stress generated in granulosa cells of antral follicles. PMID:25409908

  17. The Adenovirus E1A Proteins Induce Apoptosis, which is Inhibited by the E1B 19-kDa and Bcl2 Proteins

    Microsoft Academic Search

    Lakshmi Rao; Michael Debbas; Peter Sabbatini; David Hockenbery; Stanley Korsmeyer; Eileen White

    1992-01-01

    Cooperation between the adenovirus E1A and E1B oncogenes is required for transformation of primary quiescent rodent cells. Although expression of E1A alone will stimulate cell proliferation sufficient to initiate transformed focus formation, proliferation fails to be sustained and foci degenerate. Coexpression of either the 19-kDa or 55-kDa E1B oncoproteins with E1A permits high-frequency transformation by overcoming this cytotoxic response. Without

  18. Progress towards cavity induced transparency

    E-print Network

    Li, Tracy (Tracy Yang)

    2010-01-01

    Inspired by electromagnetically induced transparency (EIT), cavity induced transparency (CIT) uses a cavity rather than a laser to couple a ground state with the excited state of a three-level system. In this thesis, I ...

  19. Arsenic-induced Aurora-A activation contributes to chromosome instability and tumorigenesis

    NASA Astrophysics Data System (ADS)

    Wu, Chin-Han; Tseng, Ya-Shih; Yang, Chao-Chun; Kao, Yu-Ting; Sheu, Hamm-Ming; Liu, Hsiao-Sheng

    2013-11-01

    Arsenic may cause serious environmental pollution and is a serious industrial problem. Depending on the dosage, arsenic may trigger the cells undergoing either proliferation or apoptosis-related cell death. Because of lack of the proper animal model to study arsenic induced tumorigenesis, the accurate risk level of arsenic exposure has not been determined. Arsenic shows genotoxic effect on human beings who uptake water contaminated by arsenic. Chromosome aberration is frequently detected in arsenic exposure-related diseases and is associated with increased oxidative stress and decreased DNA repairing activity, but the underlying mechanism remains elusive. Aurora-A is a mitotic kinase, over-expression of Aurora-A leads to centrosome amplification, chromosomal instability and cell transformation. We revealed that Aurora-A is over-expressed in the skin and bladder cancer patients from blackfoot-disease endemic areas. Our cell line studies reveal that arsenic exposure between 0.5 ?M and 1 ?M for 2-7 days are able to induce Aurora-A expression and activation based on promoter activity, RNA and protein analysis. Aurora-A overexpression further increases the frequency of unsymmetrical chromosome segregation through centrosome amplification followed by cell population accumulated at S phase in immortalized keratinocyte (HaCaT) and uroepithelial cells (E7). Furthermore, Aurora-A over-expression was sustained for 1-4 weeks by chronic treatment of immortalized bladder and skin cells with NaAsO2. Aurora-A promoter methylation and gene amplification was not detected in the long-term arsenic treated E7 cells. Furthermore, the expression level of E2F1 transcription factor (E2F1) is increased in the presence of arsenic, and arsenic-related Aurora-A over-expression is transcriptionally regulated by E2F1. We further demonstrated that overexpression of Aurora-A and mutant Ha-ras or Aurora-A and mutant p53 may act additively to trigger arsenic-related bladder and skin cancer formation, respectively. It indicates that from chromosome instability proceeding to tumorigenesis, the simultaneous action of Aurora-A with activated oncogenic factor or inactivated tumor suppressor is required. In summary, we hypothesize that low concentration (0.5-1 ?M) of arsenic-induced E2F1-Aurora-A signaling pathway results in aberrant chromosome distribution during cell mitosis, the abnormal mitotic cells proceed to cancer cells only after acquiring additional tumorigenic factors. Our studies suggest that inhibition of low concentration of arsenic induced Aurora-A expression may provide a new theraputical strategy for the prevention and treatment of arsenic-related cancers.

  20. Flow-induced vibration - 1986

    Microsoft Academic Search

    S. S. Chen; J. C. Simonis; Y. S. Shin

    1986-01-01

    This book presents the papers given at a conference which examined mechanical vibrations in pipes caused by fluid flow. Topics considered at the conference included fluid excitation forces, axial flow induced vibration, fluid damping, crossflow induced vibration of multiple cylinders, two-phase flow, a computer program for vibration analysis, hydrodynamics, heat exchangers, and flow-induced vibrations of condenser tubes.

  1. Ellipticity induced Alfven eigenmodes

    SciTech Connect

    Betti, R.; Freidberg, J.P. (Massachusetts Institute of Technology, Plasma Fusion Center, Cambridge, Massachusetts 02139 (US))

    1991-08-01

    It is shown that noncircularity of tokamak flux surfaces leads to frequency gaps in the magnetohydrodynamic Alfven continuum. Within these gaps discrete modes having macroscopic structure are shown to exist and have many common features with toroidicity induced Alfven eigenmodes. The present work focuses on ellipticity. Since {kappa}{minus}1{gt}{epsilon} in many tokamaks the ellipticity induced Alfven eigenmode may indeed be a more robust mode. The most global mode couples the {ital m}=1, {ital n}=1 and {ital m}=3, {ital n}=1 cylindrical'' eigenmodes. The region of strong coupling occurs at the {ital q}({ital r})=2 surface and the width of the coupling region is finite and of order ({kappa}{minus}1){ital a}. Furthermore, for typical limiter {ital q}({ital r}) profiles satisfying 1{approx lt}{ital q}{approx lt}3, the dominant mode harmonics do not intersect the continuum Alfven spectrum.

  2. Electromagnetically Induced Entanglement

    E-print Network

    Xihua Yang; Min Xiao

    2015-05-18

    We present a novel quantum phenomenon named electromagnetically induced entanglement in the conventional Lambda-type three-level atomic system driven by a strong pump field and a relatively weak probe field. Nearly perfect entanglement between the pump and probe fields can be achieved with a low coherence decay rate between the two lower levels, high pump-field intensity, and large optical depth of the atomic ensemble. The physical origin is quantum coherence between the lower doublet produced by the pump and probe fields, similar to the well-known electromagnetically induced transparency. This method would greatly facilitate the generation of nondegenerate narrow-band continuous-variable entanglement between bright light beams by using only coherent laser fields, and may find potential and broad applications in realistic quantum information processing.

  3. Sepsis-induced Cardiomyopathy

    PubMed Central

    Romero-Bermejo, Francisco J; Ruiz-Bailen, Manuel; Gil-Cebrian, Julián; Huertos-Ranchal, María J

    2011-01-01

    Myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to 70%. During the sepsis-induced myocardial dysfunction, both ventricles can dilate and diminish its ejection fraction, having less response to fluid resuscitation and catecholamines, but typically is assumed to be reversible within 7-10 days. In the last 30 years, It´s being subject of substantial research; however no explanation of its etiopathogenesis or effective treatment have been proved yet. The aim of this manuscript is to review on the most relevant aspects of the sepsis-induced myocardial dysfunction, discuss its clinical presentation, pathophysiology, etiopathogenesis, diagnostic tools and therapeutic strategies proposed in recent years. PMID:22758615

  4. Electromagnetically induced polarization conversion

    NASA Astrophysics Data System (ADS)

    Khanikaev, Alexander B.; Mousavi, S. Hossein; Wu, Chihhui; Dabidian, Nima; Alici, Kamil B.; Shvets, Gennady

    2012-07-01

    Electromagnetically induced transparency and polarization conversion due to interference between two polarization-selective plasmonic resonances coexisting in the same planar metamaterial are studied. The metasurface represents a periodic array of two topologically distinct metamolecules combined on the same substrate: i) monopole antennas connected to wires and supporting a high-Q resonance radiatively coupled to x-polarization, and ii) dipolar antennas supporting a low-Q resonance coupled to y-polarization. We demonstrate that due to the interaction between these modes through a capacitive coupling between the metamolecules, one can observe a circularly-polarized Electromagnetically Induced Transparency (EIT) and thereby achieve an efficient ultra-thin quarter-wave plate.

  5. Tulipalin A induced phytotoxicity.

    PubMed

    McCluskey, James; Bourgeois, Marie; Harbison, Raymond

    2014-04-01

    Tulipalin A induced phytotoxicity is a persistent allergic contact dermatitides documented in floral workers exposed to Alstroemeria and its cultivars.[1] The causative allergen is tulipalin A, a toxic glycoside named for the tulip bulbs from which it was first isolated.[2] The condition is characterized by fissured acropulpitis, often accompanied by hyperpigmentation, onychorrhexis, and paronychia. More of the volar surface may be affected in sensitized florists. Dermatitis and paronychia are extremely common conditions and diagnostic errors may occur. A thorough patient history, in conjunction with confirmatory patch testing with a bulb sliver and tuliposide A exposure, can prevent misdiagnosis. We report a case of Tulipalin A induced phytotoxicity misdiagnosed as an unresolved tinea manuum infection in a patient evaluated for occupational exposure. PMID:25024947

  6. DAW22, a natural sesquiterpene coumarin isolated from Ferula ferulaeoides (Steud.) Korov. that induces C6 glioma cell apoptosis and endoplasmic reticulum (ER) stress.

    PubMed

    Zhang, Lan; Tong, Xupeng; Zhang, Jin; Huang, Jian; Wang, Jinhui

    2015-06-01

    2,3-Dihydro-7-hydroxy-2R*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c]coumarin (named DAW22), a sesquiterpene coumarin isolated from the roots of Ferula ferulaeoides (Steud.) Korov., has been reported to bear anti-proliferative activities toward different types of cancer cells. In this study, we demonstrated that DAW22 induced apoptosis in C6 glioma cells. Subsequently, we found that DAW22-induced apoptosis in C6 glioma cells occurred via the mitochondria-mediated and death-receptor pathways. Moreover, we found a massive cytoplasmic vacuolization, a dramatic change of endoplasmic reticulum (ER), up-regulation of CHOP and cleavage of caspase-12, suggesting that DAW22-induced apoptosis is involved in ER stress. In addition, we revealed that DAW22 treatment induced the activation of PERK, ATF6? and IRE1?. We further found that knockdown of CHOP affected DAW22-induced apoptosis, and DAW22-stimulated down-regulation of Bcl-2, caspase-8 activation and PARP cleavage were inhibited. Taken together, these results demonstrate that DAW22 induces apoptosis by ER stress and mitochondrial/death-receptor pathways, which may provide a new clue for exploiting this compound as a potential anti-neoplastic drug in future glioma cancer therapy. PMID:25776007

  7. Methods for Inducing Pluripotency

    Microsoft Academic Search

    Raymond L. Page; Christopher Malcuit; Tanja Dominko

    \\u000a Induced pluripotent stem (iPS) cells are embryonic stem-like cells produced by forcing expression of a minimal number of key\\u000a factors in differentiated somatic cells. In many ways, they are indistinguishable from embryonic stem cells in that they can\\u000a differentiate into any cell type in the body. This development has led to worldwide excitement over the possibility to develop\\u000a cell-based therapies

  8. Environment induced incoherent controllability

    E-print Network

    Raffaele Romano; Domenico D'Alessandro

    2005-11-08

    We prove that the environment induced entanglement between two non interacting, two-dimensional quantum systems S and P can be used to control the dynamics of S by means of the initial state of P. Using a simple, exactly solvable model, we show that both accessibility and controllability of S can be achieved under suitable conditions on the interaction of S and P with the environment.

  9. Tumor-induced osteomalacia

    Microsoft Academic Search

    Daniel Schapira; Ofer Ben Izhak; Alicia Nachtigal; Amira Burstein; Rachel Bar Shalom; Ibrahim Shagrawi; Lael Anson Best

    1995-01-01

    Tumor-induced (oncogenic) osteomalacia is a rare clinicopathologic entity inwhich the clinical signs and symptoms of osteomalacia and the specific laboratory abnormalities of hypophosphatemia, hyperphosphaturia, and low serum levels of 1,25(OH)2 vitamin D are associated with the finding of a neoplastic process in the patient. To date, less than 100 cases of oncogenic osteomalacia have been described. We report a new

  10. Food-Induced Anaphylaxis

    Microsoft Academic Search

    Kirsi M. Järvinen-Seppo; Anna Nowak-W?grzyn

    \\u000a Food allergy is the most common single cause of anaphylaxis. About 4–6% of children and 3% of adults suffer from confirmed\\u000a food allergy, which places a huge population at risk for anaphylaxis. This chapter provides an overview of the epidemiology,\\u000a pathophysiology, clinical presentation, pediatric considerations, risk factors, treatment, diagnosis, prevention, and natural\\u000a history of food-induced anaphylaxis. With a growing population

  11. Drug-induced phospholipidosis

    Microsoft Academic Search

    K.-U. Seiler; O. Wassermann

    1975-01-01

    In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid\\/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on

  12. Tattoo-induced psoriasis.

    PubMed

    Orzan, O A; Popa, L G; Vexler, E S; Olaru, I; Voiculescu, V M; Bumb?cea, R S

    2014-01-01

    Koebner phenomenon represents the development of several inflammatory skin lesions (psoriasis, lichen planus, vitiligo, etc.) in uninvolved skin following various traumatic insults. The case of a 27-year-old male patient with scalp psoriasis who was referred to our clinic for generalized psoriatic lesions developed two weeks after tattooing his skin at the age of 18 was presented; the case illustrated the possibility of Koebner phenomenon induced by skin tattooing in patients with psoriasis. PMID:25870676

  13. Mastication induced retrobulbar hemorrhage.

    PubMed

    Tran, Kimberly D; Scawn, Richard L; Whipple, Katherine M; Korn, Bobby S; Kikkawa, Don O

    2013-12-01

    Retrobulbar hemorrhage is a feared potentially sight threatening complication after orbital decompression surgery. We present a patient, 36 hours after surgery, while forcefully biting, suddenly developed a retrobulbar hemorrhage arising from the temporalis muscle causing an orbital compartment syndrome. Rapid intervention with canthotomy and cantholysis was associated with recovery of vision from absent light perception to 20/20. A mastication induced retrobulbar hemorrhage has not been previously described. PMID:23957737

  14. Allergen-induced asthma

    PubMed Central

    Cockcroft, Donald W

    2014-01-01

    It was only in the late 19th century that specific allergens, pollen, animal antigens and, later, house dust mite, were identified to cause upper and lower airway disease. Early allergen challenge studies, crudely monitored before measurement of forced expiratory volume in 1 s became widespread in the 1950s, focused on the immediate effects but noted in passing prolonged and/or recurrent asthma symptoms. The late asthmatic response, recurrent bronchoconstriction after spontaneous resolution of the early responses occurring 3 h to 8 h or more postchallenge, has been identified and well characterized over the past 50 years. The associated allergen-induced airway hyper-responsiveness (1977) and allergen-induced airway inflammation (1985) indicate that these late sequelae are important in the mechanism of allergen-induced asthma. Allergens are now recognized to be the most important cause of asthma. A standardized allergen inhalation challenge model has been developed and is proving to be a valuable research tool in the investigation of asthma pathophysiology and of potential new pharmacological agents for the treatment of asthma. PMID:24791256

  15. Study of cavitating inducer instabilities

    NASA Technical Reports Server (NTRS)

    Young, W. E.; Murphy, R.; Reddecliff, J. M.

    1972-01-01

    An analytic and experimental investigation into the causes and mechanisms of cavitating inducer instabilities was conducted. Hydrofoil cascade tests were performed, during which cavity sizes were measured. The measured data were used, along with inducer data and potential flow predictions, to refine an analysis for the prediction of inducer blade suction surface cavitation cavity volume. Cavity volume predictions were incorporated into a linearized system model, and instability predictions for an inducer water test loop were generated. Inducer tests were conducted and instability predictions correlated favorably with measured instability data.

  16. Steam Condensation Induced Waterhammer 

    E-print Network

    Kirsner, W.

    2000-01-01

    of heat. Wayne was knocked down and stunned by the scalding water spraying from the valve. Egress via the manhole exit was cut offby steam spraying from the valve. The only way out appeared to be through the material passouts constructed into the roof... exceed 1000 psi. This is enough pressure to fracture a cast iron valve. blowout a steam gasket, or burst an accordion type expansion joint. And. in fact. failure ofeach ofthese compo nents in separate condensation induced water hammer accidents has...

  17. Stress-induced cardiomyopathy.

    PubMed

    Lisung, Fausto Gabriel; Shah, Ankit B; Levitt, Howard L; Coplan, Neil B

    2015-01-01

    A woman in her early 70s presented with chest pain, dyspnoea and diaphoresis 30 min after her husband expired in our hospital. Cardiac markers were elevated and there were acute changes in ECG suggestive for acute coronary syndrome. Echocardiogram showed apical akinesis, basal segment hyperkinesis with an ejection fraction of 30%. Cardiac catheterisation was performed showing non-obstructive coronary arteries, leading to the diagnosis of stress-induced cardiomyopathy. The patient improved with medical management. Repeat echocardiogram 2 months later showed resolution of heart failure with an ejection fraction of 65-70%. PMID:25858931

  18. Neutron Induced Beta Radiography

    SciTech Connect

    Shaikh, A. M.; Shylaja, D. [Solid State Physics Division, Bhabha Atomic Research Centre, Mumbai 400085 (India)

    2011-07-15

    In the present paper we give a new methodology named, 'neutron induced beta radiography-NIBR' which makes use of neutron activated Dy or In foils as source of (3-radiation. Radiographs are obtained with an aluminium cassette containing image plate, a sample under inspection and the activated Dy or In foil kept in tight contact. The sensitivity of the technique to thickness was evaluated for different materials in the form of step wedges. Some radiographs are presented to demonstrate potential of method to inspect thin samples.

  19. Coherence-induced entanglement

    E-print Network

    Li, F. L.; Xiong, H.; Zubairy, M. Suhail

    2005-01-01

    Coherence-induced entanglement Fu-li Li, Han Xiong, and M. Suhail Zubairy Institute for Quantum Studies and Department of Physics, Texas A&M University, College Station, Texas 77843-4242, USA #1;Received 7 March 2005; published 19 July 2005... of atomic coherence. DOI: 10.1103/PhysRevA.72.010303 PACS number#1;s#2;: 03.67.Mn, 03.65.Ud Atomic coherence #3;1#4;, which results from a coherent su- perposition of different states of a single atom, can lead to many different quantum optical phenomena...

  20. Antioxidant-induced stress.

    PubMed

    Villanueva, Cleva; Kross, Robert D

    2012-01-01

    Antioxidants are among the most popular health-protecting products, sold worldwide without prescription. Indeed, there are many reports showing the benefits of antioxidants but only a few questioning the possible harmful effects of these "drugs". The normal balance between antioxidants and free radicals in the body is offset when either of these forces prevails. The available evidence on the harmful effects of antioxidants is analyzed in this review. In summary, a hypothesis is presented that "antioxidant-induced stress" results when antioxidants overwhelm the body's free radicals. PMID:22408440

  1. Method for inducing hypothermia

    DOEpatents

    Becker, Lance B. (Chicago, IL); Hoek, Terry Vanden (Chicago, IL); Kasza, Kenneth E. (Palos Park, IL)

    2008-09-09

    Systems for phase-change particulate slurry cooling equipment and methods to induce hypothermia in a patient through internal and external cooling are provided. Subcutaneous, intravascular, intraperitoneal, gastrointestinal, and lung methods of cooling are carried out using saline ice slurries or other phase-change slurries compatible with human tissue. Perfluorocarbon slurries or other slurry types compatible with human tissue are used for pulmonary cooling. And traditional external cooling methods are improved by utilizing phase-change slurry materials in cooling caps and torso blankets.

  2. Method for inducing hypothermia

    DOEpatents

    Becker, Lance B.; Hoek, Terry Vanden; Kasza, Kenneth E.

    2005-11-08

    Systems for phase-change particulate slurry cooling equipment and methods to induce hypothermia in a patient through internal and external cooling are provided. Subcutaneous, intravascular, intraperitoneal, gastrointestinal, and lung methods of cooling are carried out using saline ice slurries or other phase-change slurries compatible with human tissue. Perfluorocarbon slurries or other slurry types compatible with human tissue are used for pulmonary cooling. And traditional external cooling methods are improved by utilizing phase-change slurry materials in cooling caps and torso blankets.

  3. Method for inducing hypothermia

    DOEpatents

    Becker, Lance B. (Chicago, IL); Hoek, Terry Vanden (Chicago, IL); Kasza, Kenneth E. (Palos Park, IL)

    2003-04-15

    Systems for phase-change particulate slurry cooling equipment and methods to induce hypothermia in a patient through internal and external cooling are provided. Subcutaneous, intravascular, intraperitoneal, gastrointestinal, and lung methods of cooling are carried out using saline ice slurries or other phase-change slurries compatible with human tissue. Perfluorocarbon slurries or other slurry types compatible with human tissue are used for pulmonary cooling. And traditional external cooling methods are improved by utilizing phase-change slurry materials in cooling caps and torso blankets.

  4. Coherence-induced entanglement 

    E-print Network

    Li, F. L.; Xiong, H.; Zubairy, M. Suhail

    2005-01-01

    Coherence-induced entanglement Fu-li Li, Han Xiong, and M. Suhail Zubairy Institute for Quantum Studies and Department of Physics, Texas A&M University, College Station, Texas 77843-4242, USA #1;Received 7 March 2005; published 19 July 2005... of atomic coherence. DOI: 10.1103/PhysRevA.72.010303 PACS number#1;s#2;: 03.67.Mn, 03.65.Ud Atomic coherence #3;1#4;, which results from a coherent su- perposition of different states of a single atom, can lead to many different quantum optical phenomena...

  5. Plant Ecology VolumE 7, NumbEr 1,

    E-print Network

    Neher, Deborah A.

    .permissions@oup.com species-dependent responses of soil microbial properties to fresh leaf inputs in a subtropical forest soil and activity of the soil microbial properties and soil carbon cycling. The objective of this study was to compare the effect of naturally fallen litter and fresh leaves on the soil microbial community composition

  6. Bacillus subtilis spores as adjuvants for DNA vaccines.

    PubMed

    Aps, Luana R M M; Diniz, Mariana O; Porchia, Bruna F M M; Sales, Natiely S; Moreno, Ana Carolina R; Ferreira, Luís C S

    2015-05-11

    Recently, Bacillus subtilis spores were shown to be endowed with strong adjuvant capacity when co-administered with purified antigenic proteins. In the present study we assessed whether spores possess adjuvant properties when combined with DNA vaccines. We showed that B. subtilis spores promoted the activation of dendritic cells in vitro and induced migration of pro-inflammatory cells after parenteral administration to mice. Likewise, co-administration of spores with a DNA vaccine encoding the human papillomavirus type 16 (HPV-16) E7 protein enhanced the activation of antigen-specific CD8(+) T cell responses in vivo. Mice immunized with the DNA vaccine admixed with spores presented a protective immunity increase to previously implanted tumor cells, capable of expressing HPV-16 oncoproteins. Finally, we observed that the adjuvant effect can vary accordingly to the number of co-administered spores which may be ascribed with the ability to induce. Collectively, the present results demonstrate for the first time that B. subtilis spores can also confer adjuvant effects to DNA vaccines. PMID:25819710

  7. Effects of HER2 over expression in human mammary epithelial cells: Evidence of altered HER2 signaling and crosstalk between insulin and EGF signaling

    Microsoft Academic Search

    Alaina Powell Boyer

    2008-01-01

    MCF10A cells express high levels of the epidermal growth factor receptor (EGFR), but low levels of HER-2, and require exogenous insulin and EGF for survival and proliferation. When HER-2 is stably over-expressed in MCF10A cells (MCF10AHER-2) the cells acquire insulin independence while still requiring exogenous EGF. Co-expression of HPV-16 oncoprotein E7 with HER-2 resulted in complete growth factor independence. We

  8. Optimum storage conditions for product of transiently expressed epitopes of Human papillomavirus using Potato virus X -based vector

    Microsoft Academic Search

    N. ?e?ovská; H. Hoffmeisterová; T. Moravec; H. Plchová; J. Folwarczna; R. Hadámková

    2008-01-01

    We describe the optimized storage conditions of recombinant Potato virus A coat protein (ACP) carrying two different epitopes from Human papillomavirus type 16 (HPV-16). Epitope derived from minor capsid protein L2 was expressed as N-terminal fusion with ACP while an epitope\\u000a derived from E7 oncoprotein was fused to its C-termini. The construct was cloned into Potato X potexvirus (PVX) based

  9. Heparin-induced thrombocytopenia.

    PubMed

    Lovecchio, F

    2014-07-01

    Abstract A summary of heparin-induced thrombocytopenia (HIT) is presented. HIT is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. The frequency of HIT ranges from 1 to 5% of patients receiving heparin with exact frequencies ranging between specific agents. Interestingly, this immune-mediated syndrome is ironically associated with thrombosis, not bleeding, with thrombin formation playing a major role. It is caused by heparin-dependent, platelet-activating antibodies that identifies a self-protein, PF4, bound to heparin that results in an antibody formation. The resulting platelet activation is associated with increased thrombin generation. Typically, the platelet count fall begins 5-10 days after starting heparin, although a rapid platelet count fall can occur in a patient who has antibodies from recent heparin use. Typical causes of HIT as well as the best diagnostic studies and treatment are discussed in this review. HIT was reviewed using a pubmed™ search; google scholar™ using key words: "Heparin-induced thrombocytopenia"; "heparin", and "drug AND thrombocytopenia." PMID:24844576

  10. Drug-Induced Lung Toxicity

    Microsoft Academic Search

    Mannfred A. Hollinger

    1993-01-01

    The number of blood-borne chemotherapeutic agents implicated in drug-induced lung toxicity continues to increase, although problems in detection remain. The initiation of drug-induced lung injury can have an immunologic or nonimmunologic basis. If endothelial cells are injured, interstitial pulmonary edema may result. Regardless of the source of injury, the progression of drug-induced lung toxicity is often quite similar, involving (1)

  11. Baboon Syndrome Induced by Hydroxyzine

    PubMed Central

    Akkari, Hayet; Belhadjali, Hichem; Youssef, Monia; Mokni, Sana; Zili, Jamelediine

    2013-01-01

    Hydroxyzine-induced drug eruptions are very rare. We report here a typical case of drug-related Baboon syndrome or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) which was induced by hydroxyzine in a 60-year-old man. The diagnosis was confirmed by positive patch and oral accidental provocation tests with hydroxyzine. Patch tests and oral provocation tests with cetirizine and levocetirizine were negative. A review of the literature identified only 17 reported cases of hydroxyzine-induced drug eruptions. To the best of our knowledge, we report here the first case of hydroxyzine-induced SDRIFE. PMID:23723506

  12. Peripherally induced oromandibular dystonia

    PubMed Central

    Sankhla, C.; Lai, E.; Jankovic, J.

    1998-01-01

    OBJECTIVES—Oromandibular dystonia (OMD) is a focal dystonia manifested by involuntary muscle contractions producing repetitive, patterned mouth, jaw, and tongue movements. Dystonia is usually idiopathic (primary), but in some cases it follows peripheral injury. Peripherally induced cervical and limb dystonia is well recognised, and the aim of this study was to characterise peripherally induced OMD.?METHODS—The following inclusion criteria were used for peripherally induced OMD: (1) the onset of the dystonia was within a few days or months (up to 1 year) after the injury; (2) the trauma was well documented by the patient's history or a review of their medical and dental records; and (3) the onset of dystonia was anatomically related to the site of injury (facial and oral).?RESULTS—Twenty seven patients were identified in the database with OMD, temporally and anatomically related to prior injury or surgery. No additional precipitant other than trauma could be detected. None of the patients had any litigation pending. The mean age at onset was 50.11 (SD 14.15) (range 23-74) years and there was a 2:1 female preponderance. Mean latency between the initial trauma and the onset of OMD was 65 days (range 1 day-1 year). Ten (37%) patients had some evidence of predisposing factors such as family history of movement disorders, prior exposure to neuroleptic drugs, and associated dystonia affecting other regions or essential tremor. When compared with 21 patients with primary OMD, there was no difference for age at onset, female preponderance, and phenomenology. The frequency of dystonic writer's cramp, spasmodic dysphonia, bruxism, essential tremor, and family history of movement disorder, however, was lower in the post-traumatic group (p<0.05). In both groups the response to botulinum toxin treatment was superior to medical therapy (p<0.005). Surgical intervention for temporomandibular disorders was more frequent in the post-traumatic group and was associated with worsening of dystonia.?CONCLUSION—The study indicates that oromandibular-facial trauma, including dental procedures, may precipitate the onset of OMD, especially in predisposed people. Prompt recognition and treatment may prevent further complications. ?? PMID:9810945

  13. Cocaine-induced pseudovasculitis.

    PubMed

    Friedman, Daphne R; Wolfsthal, Susan D

    2005-05-01

    Pseudovasculitis is a disease process that mimics the presentation and possibly the laboratory findings of true vasculitis. However, biopsy specimens do not reveal the typical histopathologic findings expected in vasculitis. One often overlooked cause of pseudovasculitis is cocaine use, which has been described in case reports to cause aggressive nasal destruction and various skin lesions and thus has been confused with Wegener granulomatosis or leukocytoclastic vasculitis. Unfortunately, serologic tests such as antinuclear antibody or antineutrophil cytoplasmic antibody cannot reliably differentiate between these entities. We describe a patient who presented with what was believed to be Wegener granulomatosis affecting the skin and upper airway. However, findings from repeated biopsies did not support this diagnosis, and the only unifying diagnosis was cocaine-induced pseudovasculitis. The ability to recognize and differentiate between true vasculitis and pseudovasculitis is essential for the clinician because treatment options are radically disparate. PMID:15887436

  14. Tumour induced osteomalacia.

    PubMed

    Masood, Muhammad Qamar; Ram, Nanik; Ali, Syed Ahsan

    2015-02-01

    Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually presenting with bone pain, fracture of bones and muscle weakness. It is caused by high serum levels of fibroblast growth factor 23 (FGF- 23), which is a hormone-regulating phosphate, and vitamin D. FGF-23 is secreted by several tumours, especially benign mesenchymal tumours which are very small and difficult to locate. There is a significant delay from onset of symptoms to the diagnosis of this entity dueto occult nature of this disease. We present a case of young male who presented with long history of progressively worsening muscular pain and weakness, rendering the patient confined to bed. Our aim of presenting this patient as a case report is to make physicians realise that any patient with unexplained muscular weakness and pain must undergo workup for TIO, including serum phosphate measurement, as this is a rare but potentially curable disease. PMID:25842564

  15. Electromagnetically Induced Transparency Spectroscopy

    E-print Network

    Eliam, Asaf; Shapiro, Moshe

    2012-01-01

    We propose a method based on the Electromagnetically Induced Transparency (EIT) phenomenon for the detection of molecules which exist as a small minority in the presence of a majority of absorbers. The EIT effect we employ effectively eliminates the absorption of the majority species in the spectral region where it overlaps with the absorption of the minority species. The method can also be used to enhance local-modes transitions which overlap spectrally with a background of other local-modes transitions of the same molecule. The general theory is applied to the case of sparse and congested background spectra within the same molecule and to the recording of the spectra of isotopomers (of Chlorine and Methanol) that are in minority relative to other isotopomers which constitute the majority of molecules present.

  16. Electromagnetically Induced Transparency Spectroscopy

    E-print Network

    Asaf Eliam; Evgeny A. Shapiro; Moshe Shapiro

    2012-01-03

    We propose a method based on the Electromagnetically Induced Transparency (EIT) phenomenon for the detection of molecules which exist as a small minority in the presence of a majority of absorbers. The EIT effect we employ effectively eliminates the absorption of the majority species in the spectral region where it overlaps with the absorption of the minority species. The method can also be used to enhance local-modes transitions which overlap spectrally with a background of other local-modes transitions of the same molecule. The general theory is applied to the case of sparse and congested background spectra within the same molecule and to the recording of the spectra of isotopomers (of Chlorine and Methanol) that are in minority relative to other isotopomers which constitute the majority of molecules present.

  17. Induced seismicity. Final report

    SciTech Connect

    Segall, P.

    1997-09-18

    The objective of this project has been to develop a fundamental understanding of seismicity associated with energy production. Earthquakes are known to be associated with oil, gas, and geothermal energy production. The intent is to develop physical models that predict when seismicity is likely to occur, and to determine to what extent these earthquakes can be used to infer conditions within energy reservoirs. Early work focused on earthquakes induced by oil and gas extraction. Just completed research has addressed earthquakes within geothermal fields, such as The Geysers in northern California, as well as the interactions of dilatancy, friction, and shear heating, on the generation of earthquakes. The former has involved modeling thermo- and poro-elastic effects of geothermal production and water injection. Global Positioning System (GPS) receivers are used to measure deformation associated with geothermal activity, and these measurements along with seismic data are used to test and constrain thermo-mechanical models.

  18. Aminoglycoside-induced nephrotoxicity.

    PubMed

    Wargo, Kurt A; Edwards, Jonathan D

    2014-12-01

    Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity. PMID:25199523

  19. [Captopril induced lichenoid eruption].

    PubMed

    Bravard, P; Barbet, M; Eich, D; Weber, M; Daniel, F; Lauret, P

    1983-01-01

    The authors report three cases of Captopril induced lichenoid eruption, already unmentionned, as far as they know. This cutaneous adverse reaction seemed to be dose related. Late onset was possible, even after six months of therapy. Violaceous papules or plaques were localized (two cases) or disseminated (one case) on the skin. The oral cavity was spared, but mucous membrane may be involved (localisation on the glans penis in one case). Histopathology was suggestive of lichen, but cellular dermal infiltrate was rather sparse. Immunofluorescent study in one case showed anti-IgM and C4 deposits on dermal colloid bodies. Captopril withdrawal was followed by improvement. Reviewing the literature, the authors are questionning about the fact that chemical structures of Penicillamine, Pyritinol and Captopril are strikingly similar and perhaps causative. PMID:6354041

  20. Herbivore induced plant volatiles

    PubMed Central

    War, Abdul Rashid; Sharma, Hari Chand; Paulraj, Michael Gabriel; War, Mohd Yousf; Ignacimuthu, Savarimuthu

    2011-01-01

    Plants respond to herbivory through different defensive mechanisms. The induction of volatile emission is one of the important and immediate response of plants to herbivory. Herbivore-induced plant volatiles (HIPVs) are involved in plant communication with natural enemies of the insect herbivores, neighboring plants, and different parts of the damaged plant. Release of a wide variety of HIPVs in response to herbivore damage and their role in plant-plant, plant-carnivore and intraplant communications represents a new facet of the complex interactions among different trophic levels. HIPVs are released from leaves, flowers, and fruits into the atmosphere or into the soil from roots in response to herbivore attack. Moreover, HIPVs act as feeding and/or oviposition deterrents to insect pests. HIPVs also mediate the interactions between the plants and the microorganisms. This review presents an overview of HIPVs emitted by plants, their role in plant defense against herbivores and their implications for pest management. PMID:22105032

  1. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Lahorte, Philippe; Mondelaers, Wim

    This chapter represents the second part of a review in which the production and application of radiation-induced radicals in biological matter are discussed. In part one the general aspects of the four stages (physical, physicochemical, chemical and biological) of interaction of radiation with matter in general and biological matter in particular, were discussed. Here an overview is presented of modem technologies and theoretical methods available for studying these radiation effects. The relevance is highlighted of electron paramagnetic resonance spectroscopy and quantum chemical calculations with respect to obtaining structural information on bioradicals, and a survey is given of the research studies in this field. We also discuss some basic aspects of modem accelerator technologies which can be used for creating radicals and we conclude with an overview of applications of radiation processing in biology and related fields such as biomedical and environmental engineering, food technology, medicine and pharmacy.

  2. Everolimus induced Pneumonitis.

    PubMed

    Badar, Q; Masood, N; Abbasi, A N

    2015-05-01

    Everolimus (RAD 001) is an orally administered inhibitor of mTOR (mammalian target of rapamycin), a central regulator of intracellular signaling pathways involved in cell growth and proliferation, cellular metabolism and angiogenesis. Drug is currently in use to prevent allograft rejection after solid organ transplantation and in treatment of advanced renal cell carcinoma (RCC). Noninfectious pneumonitis is rare adverse reaction associated with rapamycin and rapamycin analogues. Awareness of this toxicity and appropriate management is important to optimize patient safety. Here we report a case of everolimus induced pneumonitis in a 72 years old male with metastatic renal cell carcinoma (mRCC) after 4 months of commencement of everolimus. Drug was discontinued and patient was treated accordingly and discharged after 10 days of hospital admission. PMID:26003100

  3. Induced metachromasia in bull spermatozoa

    Microsoft Academic Search

    M. L. S. Mello

    1982-01-01

    The availability of sequential DNA phosphates to bind toluidine blue molecules after acid hydrolysis was studied in normally shaped and misshaped spermatozoa from subfertile and highly fertile bulls. The aim was to associate induced spermatozoal metachromasia with infertility. Some few normally and abnormally shaped cells from highly fertile bulls exhibited an induced metachromasia after being treated with 4N HCl for

  4. Fishbone-induced perforated appendicitis.

    PubMed

    Bababekov, Yanik J; Stanelle, Eric J; Abujudeh, Hani H; Kaafarani, Haytham M A

    2015-01-01

    We review the literature and describe a case of fishbone-induced appendicitis. A 63-year-old man presented with abdominal pain. Work up including a focused history and imaging revealed fishbone-induced perforated appendicitis. The patient was managed safely and successfully with laparoscopic removal of the foreign body and appendectomy. PMID:25994432

  5. Switching-induced Turing instability

    Microsoft Academic Search

    J. Buceta; Katja Lindenberg

    2002-01-01

    We propose a mechanism for inducing a Turing instability in systems whose only stable state is pattern-free and homogeneous. Global alternation between two dynamics, each of which has the same homogeneous stable state, may induce a Turing instability that leads to pattern formation. We determine what kind of alternation can drive the system to a Turing instability, and show that

  6. 4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor {gamma} agonist alleviates the symptoms of DSS-induced colitis

    SciTech Connect

    Yamamoto, Keiko [Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543 (Japan); Ninomiya, Yuichi; Iseki, Mioko [Division of Translational Research, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Nakachi, Yutaka; Kanesaki-Yatsuka, Yukiko [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Yamanoue, Yu; Itoh, Toshimasa [Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Nishii, Yasuho [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Petrovsky, Nikolai [Diabetes and Endocrinology, Flinders Medical Centre, Bedford Park, SA 5042 (Australia); Okazaki, Yasushi [Division of Translational Research, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan)], E-mail: okazaki@saitama-med.ac.jp

    2008-03-14

    (5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.

  7. Edinburgh Research Explorer Translation elongation factor eEF1A2 is a potential oncoprotein

    E-print Network

    Millar, Andrew J.

    Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, UK and 2Breast Unit Research Group, Western General Hospital, Edinburgh EH4 2XU, UK Email: Victoria

  8. The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy

    Microsoft Academic Search

    Francesca Froldi; Marcello Ziosi; Flavio Garoia; Andrea Pession; Nicola A Grzeschik; Paola Bellosta; Dennis Strand; Helena E Richardson; Annalisa Pession; Daniela Grifoni

    2010-01-01

    BACKGROUND: Neoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. Precancerous cells are often removed by cell death from normal tissues in the early steps of the tumourigenic process, but the molecules responsible for such a fundamental safeguard process remain in part elusive. With the aim to investigate the molecular crosstalk occurring

  9. Immortalization of Human Bronchial Epithelial Cells in the Absence of Viral Oncoproteins

    Microsoft Academic Search

    Ruben D. Ramirez; Shelley Sheridan; Luc Girard; Mitsuo Sato; Young Kim; Jon Pollack; Michael Peyton; Ying Zou; Jonathan M. Kurie; J. Michael DiMaio; Sara Milchgrub; Alice L. Smith; Rhonda F. Souza; Laura Gilbey; Xi Zhang; Kenia Gandia; Melville B. Vaughan; Woodring E. Wright; Adi F. Gazdar; Jerry W. Shay; John D. Minna

    2004-01-01

    By expressing two genes (hTERT and Cdk4), we have developed a method to reproducibly generate continuously replicating human bron- chial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells. Twelve human bronchial epithelial biopsy specimens ob- tained from persons with and without lung cancer were

  10. Tyrosines 1015 and 1062 Are in Vivo Autophosphorylation Sites in Ret and Ret-Derived Oncoproteins

    Microsoft Academic Search

    DOMENICO SALVATORE; MARIA VITTORIA BARONE; GIULIANA SALVATORE; ROSA MARINA MELILLO; GENNARO CHIAPPETTA; ALBA MINEO; GIANFRANCO FENZI; GIANCARLO VECCHIO; ALFREDO FUSCO; MASSIMO SANTORO

    2010-01-01

    Point mutations of the RET receptor tyrosine kinase are respon- sible for the inheritance of multiple endocrine neoplasia (MEN) type 2 syndromes and are also present in a fraction of sporadic medullary thyroid carcinomas. Somatic rearrangements of the RET gene gen- erating the chimeric RET\\/papillary thyroid carcinoma (PTC) onco- genes are the predominant molecular lesions associated with papil- lary carcinoma,

  11. TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein

    PubMed Central

    Bhatnagar, Sanchita; Gazin, Claude; Chamberlain, Lynn; Ou, Jianhong; Zhu, Xiaochun; Tushir, Jogender S.; Virbasius, Ching-Man; Lin, Ling; Zhu, Lihua J.; Wajapeyee, Narendra; Green, Michael R.

    2014-01-01

    The TRIM37 (or MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to ~40% of breast cancers1. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases2, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression3. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF23,4 (also called RING1B) is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumour suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A (H2A-ub). However, unlike RNF2, which is a subunit of Polycomb repressive complex 1 (PRC1)3–5, we find that TRIM37 associates with Polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to specific target genes resulting in their transcriptional silencing. RNA interference (RNAi)-mediated knockdown of TRIM37 results in loss of H2A-ub, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantially decreases tumour growth in mouse xenografts. Conversely, ectopic expression of TRIM37 renders non-transformed cells tumorigenic. Collectively, our results reveal TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumour suppressors and other genes. PMID:25470042

  12. Subcellular and submitochondrial mode of action of Bcl2-like oncoproteins

    Microsoft Academic Search

    Naoufal Zamzami; Catherine Brenner; Isabel Marzo; Santos A Susin; Guido Kroemer; G Kroemer

    1998-01-01

    Bcl-2 is the prototype of a class of oncogenes which regulates apoptosis. Bcl-2-related gene products with either death-promoting and death-inhibitory activity are critically involved in numerous disease states and thus constitute prime targets for therapeutic interventions. The relative amount of death agonists and antagonists from the Bcl-2 family constitutes a regulatory rheostat whose function is determined, at least in part,

  13. CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation

    PubMed Central

    Puustinen, Pietri; Rytter, Anna; Mortensen, Monika; Kohonen, Pekka; Moreira, José M.

    2014-01-01

    mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. This regulatory circuit is reversed by ubiquitination and p62/SQSTM1-dependent autophagic degradation of CIP2A and subsequent inhibition of mTORC1 activity. Consistent with CIP2A’s reported ability to protect c-Myc against proteasome-mediated degradation, autophagic degradation of CIP2A upon mTORC1 inhibition leads to destabilization of c-Myc. These data characterize CIP2A as a distinct regulator of mTORC1 and reveals mTORC1-dependent control of CIP2A degradation as a mechanism that links mTORC1 activity with c-Myc stability to coordinate cellular metabolism, growth, and proliferation. PMID:24590173

  14. High resolution imaging &HPV oncoprotein detection for global prevention of cerv | Division of Cancer Prevention

    Cancer.gov

    Skip to main content Division of Cancer Prevention Search form Search Main menu Home Major Programs Research Networks Map Alliance of Glycobiologists for Detection of Cancer Barrett's Esophagus Translational Research Network (BETRNet) Cancer Prevention

  15. Role of the Leucine Zipper of Marek's Disease Virus Oncoprotein Meq in Pathogenesis 

    E-print Network

    Suchodolski, Paulette F.

    2010-07-14

    Md5?Meq infected chickens 14 dpi................................................. 51 12 Detection of MDV pp38 protein in latently infected cels 21 dpi........ 52 13 Mortality in chickens inoculated with rMd5, rMd5-MeqGCN, and rd5?Meq..., significant proportions of afected chickens also had visceral lymphomas, which were cytologicaly similar to the lymphoid infiltrations in nervous tisue. These occurrences of visceral tumors in MD lead to confusion with lymphoid leukosis (6). Leukosis...

  16. Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells

    Microsoft Academic Search

    E-H Park; S S Koh; R Srisuttee; I-R Cho; H-J Min; B H Jhun; Y-S Lee; K L Jang; C-H Kim; R N Johnston; Y-H Chung

    2009-01-01

    Although reovirus has been used in tests as a potential cancer therapeutic agent against a variety of cancer cells, its application to hepatocellular carcinoma cells, in which the hepatitis B virus (HBV) X (HBX) protein of HBV plays a primary role, has not yet been explored. Here, we describe experiments in which we use reovirus to treat Chang liver carcinoma

  17. Role of the Leucine Zipper of Marek's Disease Virus Oncoprotein Meq in Pathogenesis

    E-print Network

    Suchodolski, Paulette F.

    2010-07-14

    Marek's disease virus (MDV), the etiologic agent of Marek's disease, is a potent oncogenic herpesvirus. MDV is highly contagious and elicits a rapid onset of malignant T-cell lymphomas in chickens within several weeks after infection. The MDV genome...

  18. Adenovirus E1B 55-Kilodalton Oncoprotein Inhibits p53 Acetylation by PCAF

    Microsoft Academic Search

    YUE LIU; APRIL L. COLOSIMO; XIANG-JIAO YANG; DAIQING LIAO

    2000-01-01

    The adenovirus E1B 55-kDa protein binds to cellular tumor suppressor p53 and inactivates its transcrip- tional transactivation function. p53 transactivation activity is dependent upon its ability to bind to specific DNA sequences near the promoters of its target genes. It was shown recently that p53 is acetylated by transcriptional coactivators p300, CREB bidning protein (CBP), and PCAF and that acetylation

  19. Laser induced ignition

    NASA Astrophysics Data System (ADS)

    Liedl, G.; Schuöcker, D.; Geringer, B.; Graf, J.; Klawatsch, D.; Lenz, H. P.; Piock, W. F.; Jetzinger, M.; Kapus, P.

    2007-05-01

    Nowadays, combustion engines and other combustion processes play an overwhelming and important role in everyday life. As a result, ignition of combustion processes is of great importance, too. Usually, ignition of a combustible material is defined in such a way that an ignition initiates a self-sustained reaction which propagates through the inflammable material even in the case that the ignition source has been removed. In most cases, a well defined ignition location and ignition time is of crucial importance. Spark plugs are well suited for such tasks but suffer from some disadvantages, like erosion of electrodes or restricted positioning possibilities. In some cases, ignition of combustible materials by means of high power laser pulses could be beneficial. High power lasers offer several different possibilities to ignite combustible materials, like thermal ignition, resonant ignition or optical breakdown ignition. Since thermal and resonant ignitions are not well suited on the requirements mentioned previously, only optical breakdown ignition will be discussed further. Optical breakdown of a gas within the focal spot of a high power laser allows a very distinct localization of the ignition spot in a combustible material. Since pulse duration is usually in the range of several nanoseconds, requirements on the ignition time are fulfilled easily, too. Laser peak intensities required for such an optical breakdown are in the range of 10 11 W/cm2. The hot plasma which forms during this breakdown initiates the following self-propagating combustion process. It has been shown previously that laser ignition of direct injection engines improves the fuel consumption as well as the exhaust emissions of such engines significantly. The work presented here gives a brief overview on the basics of laser induced ignition. Flame propagation which follows a successful ignition event can be distinguished into two diffrent regimes. Combustion processes within an engine are usually quite slow - the reaction velocity is mainly determined by the heat conductivity of the combustible. Such deflagrations processes show propagation velocities well below the speed of sound. On the other hand, detonations show much higher propagation velocities. In contrast to deflagrations, detonations show propagation velocities higher than the speed of sound within the combustible. The shock front which propagates through a combustible in the case of a detonation is responsible for a considerable pressure gradient moving at supersonic velocity. Basics and possible examples of laser induced ignitions of deflagrations and detonations are given and pros and cons of laser ignition systems are discussed briefly.

  20. Noise-Induced Hearing Loss among Adults

    MedlinePLUS

    ... Noise-Induced Hearing Loss Among Adults Noise-Induced Hearing Loss Among Adults [text version] Note: Lower numbers are ... chart depicts the prevalence of likely noise-induced hearing loss from 2 time periods in adults (20–69 ...

  1. Electromagnetically Induced Flows Michiel de Reus

    E-print Network

    Vuik, Kees

    Electromagnetically Induced Flows in Water Michiel de Reus 8 maart 2013 () Electromagnetically Conclusion and future research () Electromagnetically Induced Flows 2 / 56 #12;1 Introduction 2 Maxwell Navier Stokes equations 5 Simulations 6 Conclusion and future research () Electromagnetically Induced

  2. Polyploidy Induces Centromere Association

    PubMed Central

    Martinez-Perez, Enrique; Shaw, Peter J.; Moore, Graham

    2000-01-01

    Many species exhibit polyploidy. The presence of more than one diploid set of similar chromosomes in polyploids can affect the assortment of homologous chromosomes, resulting in unbalanced gametes. Therefore, a mechanism is required to ensure the correct assortment and segregation of chromosomes for gamete formation. Ploidy has been shown to affect gene expression. We present in this study an example of a major effect on a phenotype induced by ploidy within the Triticeae. We demonstrate that centromeres associate early during anther development in polyploid species. In contrast, centromeres in diploid species only associate at the onset of meiotic prophase. We propose that this mechanism provides a potential route by which chromosomes can start to be sorted before meiosis in polyploids. This explains previous reports indicating that meiotic prophase is shorter in polyploids than in their diploid progenitors. Even artificial polyploids exhibit this phenotype, suggesting that the mechanism must be present in diploids, but only expressed in the presence of more than one diploid set of chromosomes. PMID:10648555

  3. Tumor-induced osteomalacia

    PubMed Central

    Chong, William H; Molinolo, Alfredo A; Chen, Clara C; Collins, Michael T

    2012-01-01

    Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1?-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed. PMID:21490240

  4. Exercise-induced anaphylaxis.

    PubMed

    Sheffer, A L; Austen, K F

    1980-08-01

    Sixteen patients were seen because of possibly life-threatening exercise-associated symptoms similar to anaphylactic reactions. Asthma attacks, cholinergic urticaria and angioedema, and cardiac arrythmias are recognized as exertion-related phenomena in predisposed patients but are distinct from the syndrome described here. A syndrome characterized by the exertion-related onset of cutaneous pruritus and warmth, the development of generalized urticaria, and the appearance of such additional manifestations as collapse in 12 patients, gastrointestinal tract symptoms in five patients, and upper respiratory distress in 10 patients has been designated exercise-induced anaphylaxis, because of the striking similarity of this symptom complex to the anaphylactic syndrome elicited by ingestion or injection of a foreign antigenic substance. There is a family history of atopic desease for 11 patients and cold urticaria for two others and a personal history of atopy in six. The size of the wheals, the failure to develop an attack with a warm bath or shower or a fever, and the prominence of syncope rule against the diagnosis of conventional cholinergic urticaria. There is no history or evidence of an encounter with an environmental source of antigen during the exercise period. PMID:7400473

  5. Contrast-induced Nephropathy

    PubMed Central

    Mohammed, Nazar M. A.; Mahfouz, Ahmed; Achkar, Katafan; Rafie, Ihsan M.; Hajar, Rachel

    2013-01-01

    Contrast-induced nephropathy (CIN) is a serious complication of angiographic procedures resulting from the administration of contrast media (CM). It is the third most common cause of hospital acquired acute renal injury and represents about 12% of the cases. CIN is defined as an elevation of serum creatinine (Scr) of more than 25% or ?0.5 mg/dl (44 ?mol/l) from baseline within 48 h. More sensitive markers of renal injury are desired, therefore, several biomarkers of tubular injury are under evaluation. Multiple risk factors may contribute to the development of CIN; these factors are divided into patient- and procedure-related factors. Treatment of CIN is mainly supportive, consisting mainly of careful fluid and electrolyte management, although dialysis may be required in some cases. The available treatment option makes prevention the corner stone of management. This article will review the recent evidence concerning CIN incidence, diagnosis, and prevention strategies as well as its treatment and prognostic implications. PMID:24696755

  6. Fission-induced plasmas

    NASA Technical Reports Server (NTRS)

    Harries, W. L.; Shiu, Y. J.

    1979-01-01

    The possibility of creating a plasma from fission fragments, and to utilize the energy of the particles to create population inversion that would lead to laser action is investigated. An investigation was made of various laser materials which could be used for nuclear-pumped lasing. The most likely candidate for a fissioning material in the gaseous form is uranium hexafluoride - UF6, and experiments were performed to investigate materials that would be compatible with it. One of the central problems in understanding a fission-induced plasma is to obtain a model of the electron behavior, and some preliminary calculations are presented. In particular, the rates of various processes are discussed. A simple intuitive model of the electron energy distribution function is also shown. The results were useful for considering a mathematical model of a nuclear-pumped laser. Next a theoretical model of a (3)He-Ar nuclear-pumped laser is presented. The theory showed good qualitative agreement with the experimental results.

  7. Methaemoglobinemia Induced by MDMA?

    PubMed

    Verhaert, L L W

    2011-01-01

    Case. A 45-year-old man with a blank medical history presented at the emergency room with dizziness and cyanosis. Physical examination showed cyanosis with a peripheral saturation (SpO(2)) of 85%, he did not respond to supplemental oxygen. Arterial blood gas analysis showed a striking chocolate brown colour. Based on these data, we determined the arterial methaemoglobin concentration. This was 32%. We gave 100% oxygen and observed the patient in a medium care unit. The next day, patient could be discharged in good condition. Further inquiry about exhibitions and extensive history revealed that the patient used MDMA (3,4- methylenedioxymethamphetamine, the active ingredient of ecstasy). Conclusion. Acquired methaemoglobinemia is a condition that occurs infrequently, but is potentially life threatening. Different nutrients, medications, and chemicals can induce methaemoglobinemia by oxidation of haemoglobin. The clinical presentation of a patient with methaemoglobinemia is due to the impossibility of O(2) binding and transport, resulting in tissue hypoxia. Important is to think about methaemoglobin in a patient who presents with cyanosis, a peripheral saturation of 85% that fails to respond properly to the administration of O(2). Because methaemoglobin can be reduced physiologically, it is usually sufficient to remove the causative agent, to give O(2), and to observe the patient. PMID:22937427

  8. Carbimazole-induced lupus

    PubMed Central

    Haq, Ihteshamul; Sosin, Michael D; Wharton, Simon; Gupta, Anindya

    2013-01-01

    We describe the case of a 50-year-old lady admitted with a 3-week history of dyspnoea and left-sided pleuritic pain associated with pleural effusion. This common clinical picture nevertheless gave rise to a significant diagnostic challenge. The medical history included a diagnosis of thyrotoxicosis made 6?months previously that was being treated with carbimazole by her general practitioner. Key-investigation results were as follows: (1) pleural fluid was sterile and exudative, with no malignant cells, (2) erythrocyte sedimentation rate, C reactive protein and D-dimer were raised, (3) antinuclear antibody, anti-dsDNA and antihistone antibodies were newly positive, (4) imaging revealed a large left ventricular mass consistent with thrombus in the absence of evidence of a myocardial infarction. Based on the above investigations we hypothesised that carbimazole had induced systemic lupus erythematosus, manifesting as serositis resulting in an exudative pleural effusion and a proinflammatory/prothrombotic state. Carbimazole was stopped. The patient's pleural effusion completely resolved and she remains asymptomatic. PMID:23391946

  9. [Hypertriglyceridemia-induced pancreatitis].

    PubMed

    Nagayama, Daiji; Shirai, Kohji

    2013-09-01

    In Japan, the frequency of acute pancreatitis is 27.7 per 100,000, which includes 1.4 % of hypertriglyceridemia-induced pancreatitis(HTGP). Severity and complication rates with HTGP have been reported as higher in comparison to acute pancreatitis from other etiologies. Havel has suggested that hydrolysis of excessive triglyceride-rich lipoproteins releases high concentrations of free fatty acid(FFA). The FFA micelles injure the vascular endothelium and acinar cells of the pancreas, producing a self-perpetuating ischemic and acidic environment with resultant toxicity. Lipoprotein lipase (LPL) abnormality has been reported to contribute to severe hypertriglyceridemia. However, patients without any LPL abnormality are often encountered clinically, suggesting that other factors may be involved in the development of severe hypertriglyceridemia. In 21 patients with HTGP, 9 patients(42.9 %) with apolipoprotein AV (ApoAV) Gly185-Cys polymorphism were observed, whereas 14.3 % with LPL gene variants. No patient had ApoCII deficiency. These results suggest that in addition to LPL gene variants, ApoAV variant may be numerously involved in HTGP. It is important for clinicians to routinely investigate pathogenesis of hypertriglyceridemia in case with pancreatitis because specific management may be needed. PMID:24205721

  10. Glucocorticoid-Induced Reversal of Interleukin-1?-Stimulated Inflammatory Gene Expression in Human Oviductal Cells

    PubMed Central

    Haw, Robin; Stein, Lincoln; Brown, Theodore J.

    2014-01-01

    Studies indicate that high-grade serous ovarian carcinoma (HGSOC), the most common epithelial ovarian carcinoma histotype, originates from the fallopian tube epithelium (FTE). Risk factors for this cancer include reproductive parameters associated with lifetime ovulatory events. Ovulation is an acute inflammatory process during which the FTE is exposed to follicular fluid containing both pro- and anti-inflammatory molecules, such as interleukin-1 (IL1), tumor necrosis factor (TNF), and cortisol. Repeated exposure to inflammatory cytokines may contribute to transforming events in the FTE, with glucocorticoids exerting a protective effect. The global response of FTE cells to inflammatory cytokines or glucocorticoids has not been investigated. To examine the response of FTE cells and the ability of glucocorticoids to oppose this response, an immortalized human FTE cell line, OE-E6/E7, was treated with IL1?, dexamethasone (DEX), IL1? and DEX, or vehicle and genome-wide gene expression profiling was performed. IL1? altered the expression of 47 genes of which 17 were reversed by DEX. DEX treatment alone altered the expression of 590 genes, whereas combined DEX and IL1? treatment altered the expression of 784 genes. Network and pathway enrichment analysis indicated that many genes altered by DEX are involved in cytokine, chemokine, and cell cycle signaling, including NF?? target genes and interacting proteins. Quantitative real time RT-PCR studies validated the gene array data for IL8, IL23A, PI3 and TACC2 in OE-E6/E7 cells. Consistent with the array data, Western blot analysis showed increased levels of PTGS2 protein induced by IL1? that was blocked by DEX. A parallel experiment using primary cultured human FTE cells indicated similar effects on PTGS2, IL8, IL23A, PI3 and TACC2 transcripts. These findings support the hypothesis that pro-inflammatory signaling is induced in FTE cells by inflammatory mediators and raises the possibility that dysregulation of glucocorticoid signaling could contribute to increased risk for HGSOC. PMID:24848801

  11. Does stress induce bowel dysfunction?

    PubMed

    Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y

    2014-08-01

    Psychological stress is known to induce somatic symptoms. Classically, many gut physiological responses to stress are mediated by the hypothalamus-pituitary-adrenal axis. There is, however, a growing body of evidence of stress-induced corticotrophin-releasing factor (CRF) release causing bowel dysfunction through multiple pathways, either through the HPA axis, the autonomic nervous systems, or directly on the bowel itself. In addition, recent findings of CRF influencing the composition of gut microbiota lend support for the use of probiotics, antibiotics, and other microbiota-altering agents as potential therapeutic measures in stress-induced bowel dysfunction. PMID:24881644

  12. Melt emplacement induced stresses

    NASA Astrophysics Data System (ADS)

    Wallner, Herbert; Schmeling, Harro

    2015-04-01

    Transport of melt into and through the lithosphere has an essential influence on it's state, evolution and properties. Rock deformation, physically seen as viscous flow, acts on a long time scale compared with the rapid ascent of melt originating in the asthenosphere. In our numerical models the short time scale transfer of melt is replaced by melt extraction and emplacement at a given depth zone above the source region. New findings reveal probably consequential stresses in the high viscous lithosphere. Thermo-mechanical physics of visco-plastic flow is approximated by Finite Difference Method with markers in an Eulerian formulation in two dimensions. The equations of conservation of mass, momentum and energy are solved for a multi component and two phase system: fluid and matrix. The full compaction formulation is used. The high Prandtl number approximation is applied, elasticity is neglected, and rheology is temperature-, stress- and depth-dependent. In consideration of depletion and enrichment melting and solidification are controlled by a simplified linear binary solid solution model. Extraction and emplacement of melt is accounted for. A continental rift scenario serves to define a model comprising asthenosphere and lithosphere under extensional conditions. A temperature anomaly generates deep melt intruding the lithosphere on its way up. We focus on the early phase of melting, forming a first plume and releasing some melt. Above a fraction limit melt extraction induces underpressure at its origin region attracting ambient melt and contracting the matrix. A melt fraction minimum develops in the inital batch. In the emplacement zone above sudden dilatation, immediate freezing, increase of enrichment and heating takes place. The dilatation of the rock matrix generates relative high stresses if it's viscosity is high. The behaviour is not intuitively comprehensible. Results are compared with numerical solutions of Compaction Boussinesq Approximation.

  13. Biomaterial-Induced Sarcoma

    PubMed Central

    Kirkpatrick, C. James; Alves, Antonio; Köhler, Holger; Kriegsmann, Jörg; Bittinger, Fernando; Otto, Mike; Williams, David F.; Eloy, Rosy

    2000-01-01

    In the study of carcinogenesis most interest has focused on carcinomas, as they represent the majority of human cancers. The recognition of the adenoma-carcinoma sequence both in humans and in animal experimental models has given the field of basic oncology the opportunity to elucidate individual mechanisms in the multistep development of carcinoma. The relative scarcity of human sarcomas coupled with the lack of adequate animal models has hampered understanding of the molecular genetic steps involved. We present an experimental model in the rat in which a high incidence of malignant mesenchymal tumors arise around a subcutaneously implanted biomaterial. Nine commercially available biomaterials were implanted in a total of 490 rats of the Fischer strain for 2 years. On average, macroscopic tumors were found in 25.8% of implantation sites over a period from 26 to 110 weeks after implantation. The most frequent tumors were malignant fibrous histiocytomas and pleomorphic sarcomas, although fibrosarcomas, leiomyosarcomas, and angiosarcomas readily developed, the latter especially around polyurethane implants. Of particular interest are the results of a detailed histological study of the capsules around the implanted biomaterials without tumors. Here a spectrum of change from focal proliferative lesions through preneoplastic proliferation to incipient sarcoma could be observed. A parallel immunohistochemical study of peri-implant capsules showed that proliferating cell nuclear antigen was of particular help in identifying these atypical proliferative lesions. To our knowledge this is the first description of a sarcoma model in which preneoplastic lesions can be readily identified and also reproducibly induced. This model provides the molecular biologist with defined stages in the development of mesenchymal malignancy, with which the multistage tumorigenesis hypothesis can be tested, analogous to the well-known adenoma-carcinoma sequence. PMID:10751369

  14. Induced-charge electrokinetic phenomena

    E-print Network

    Bazant, Martin Z.

    We give a general, physical description of “induced-charge electro-osmosis” (ICEO), the nonlinear electrokinetic slip at a polarizable surface, in the context of some new techniques for microfluidic pumping and mixing. ...

  15. Electromagnetically induced transparency by NMR

    E-print Network

    Son, HyungBin, 1981-

    2004-01-01

    Electromagnetically Induced Transparency (EIT) is a quantum nonlinear optical interference effect in which light at a certain frequency makes normally opaque atomic systems transparent to light at another frequency. Recent ...

  16. Drug-induced lupus erythematosus

    MedlinePLUS

    Drug-induced lupus erythematosus is an autoimmune disorder that is brought on by a reaction to a medicine. ... to systemic lupus erythematosus (SLE). It is an autoimmune disorder. This means your body attacks healthy tissue by ...

  17. [Etiology and pathogenesis of precancerous lesions and invasive cervical carcinoma].

    PubMed

    Panjkovi?, Milana; Ivkovi?-Kapicl, Tatjana

    2008-01-01

    Cervical cancer is the second most common gynecological malignancy in the world. Human papilloma virus (HPV) infection is the leading ethiologic agent in the development of premalignant and malignant cervical diseases. HPV is a member of the Papovaviridae family and until now over 100 types have been recognized There are two types of viral infection: latent and productive. Virus induced oncogenesis is the result of interaction between virus oncoproteins E6 and E7 and tumor supresor host genes p53 and Rb. Many cofactors such as immunosuppression, early sexual relationship, multiple sexual partners, other sexualy transsmited infections and smoking are contributing factors of the precancerous and invasive cervical lesions. According to the oncogenic potential HPV are divided into three groups: low, intermediate and high oncogenic risk viruses. Molecular technics which are used for the virus detection are: In situ hibridisation, Hyybrid capture test and polymerasa chain reaction. Human papilloma virus testing has an important role in the follow up and treatment of women with "atypical squamous cells of unknown significant" changes in cervical smears and low-grade squamous intraepithelial lesions, changes in punch biopsy. PMID:19097373

  18. Persistent human papillomavirus infection and cervical neoplasia.

    PubMed

    Ferenczy, Alex; Franco, Eduardo

    2002-01-01

    The development of cervical cancer is preceded by precursor lesions (cervical intraepithelial neoplasia). Evidence-based epidemiological and molecular data suggest that persistent infections with human papillomavirus (HPV) types that carry ahigh oncogenic risk are the intermediate endpoints, leading to both intraepithelial and invasive cervical neoplasia. Integration of highly oncogenic HPVs into host-cell chromosomes is followed by binding of HPV E6 and E7 oncoproteins to tumour-suppressor genes p53 and RB, respectively. This process results in impaired tumour-suppressor-gene function, involving DNA repair, decreased apoptosis, and eventual cell immortalisation. Mutations causing chromosomal alterations, loss of heterozygosity, and proto-oncogene and telomerase activation in immunopermissive individuals have important roles in virus-induced cervical carcinogenesis. The so-called non-European variants of HPV 16 and 18 may increase the degradation potential of p53. HPV 16 is polymorphic and, although the evidence is controversial, the Arg/Arg genotype of p53 could have greater susceptibility to HPV-E6 degradation than the other genotypes. The coincident interplay between the non-European genomic variants of HPV 16/18 and p53 Arg/Arg may explain, at least in part, the persistence of HPV infection and tumour progression in women with cervical neoplasia. Further epidemiological and molecular research is needed, to gain insight into HPV-mediated cervical carcinogenesis. The evidence highlights the need to develop appropriate prophylactic HPV vaccines and diagnostic and screening tests. PMID:11905599

  19. HPV-Based Screening, Triage, Treatment, and Followup Strategies in the Management of Cervical Intraepithelial Neoplasia

    PubMed Central

    Peralta-Zaragoza, Oscar; Deas, Jessica; Gómez-Cerón, Claudia; García-Suastegui, Wendy Argelia; Fierros-Zárate, Geny del Socorro; Jacobo-Herrera, Nadia Judith

    2013-01-01

    Cervical cancer is the second most common cause of death from cancer in women worldwide, and the development of new diagnostic, prognostic, and treatment strategies merits special attention. Many efforts have been made to design new drugs and develop immunotherapy and gene therapy strategies to treat cervical cancer. HPV genotyping has potentially valuable applications in triage of low-grade abnormal cervical cytology, assessment of prognosis and followup of cervical intraepithelial neoplasia, and in treatment strategies for invasive cervical cancer. It is known that during the development of cervical cancer associated with HPV infection, a cascade of abnormal events is induced, including disruption of cellular cycle control, alteration of gene expression, and deregulation of microRNA expression. Thus, the identification and subsequent functional evaluation of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information in understanding cervical carcinogenesis, identifying cervical cancer molecular markers, and developing specific targeting strategies against tumor cells. Therefore, in this paper, we discuss the main diagnostic methods, management strategies, and followup of HPV-associated cervical lesions and review clinical trials applying gene therapy strategies against the development of cervical cancer. PMID:23690785

  20. Human papillomavirus and the development of non-melanoma skin cancer.

    PubMed Central

    Harwood, C A; McGregor, J M; Proby, C M; Breuer, J

    1999-01-01

    Human papillomaviruses (HPV) are increasingly recognised as important human carcinogens. The best established association with human malignancy is that of high-risk mucosal HPV types and anogenital cancer. HPV-induced transformation of anogenital epithelia has been the subject of intense research which has identified the cellular tumour suppressor gene products, p53 and pRB, as important targets for the viral oncoproteins E6 and E7 respectively. Certain HPV types are also strongly associated with the development of non-melanoma skin cancer in the inherited disorder epidermodysplasia verruciformis (EV). However, in contrast with anogenital malignancy the oncogenic mechanisms of EV-HPV types remain uncertain, and there appears to be a crucial additional requirement for ultraviolet radiation. Cutaneous HPV types in the general population are predominantly associated with benign viral warts, but a role in non-melanoma skin cancer has recently been postulated. Polymerase chain reaction based HPV detection techniques have shown a high prevalence of HPV DNA, particularly in skin cancers from immunosuppressed patients and to a lesser extent in malignancies from otherwise immunocompetent individuals. No particular HPV type has yet emerged as predominant, and the role of HPV in cutaneous malignancy is unclear at present. It remains to be established whether HPV plays an active or purely a passenger role in the evolution of non-melanoma skin cancer. PMID:10474513

  1. Clotiazepam-induced acute hepatitis.

    PubMed

    Habersetzer, F; Larrey, D; Babany, G; Degott, C; Corbic, M; Pessayre, D; Benhamou, J P

    1989-09-01

    We report the case of a patient who developed acute hepatitis with extensive hepatocellular necrosis, 7 months after the onset of administration of clotiazepam, a thienodiazepine derivative. Clotiazepam withdrawal was followed by prompt recovery. The administration of several benzodiazepines, chemically related to clotiazepam, did not interfere with recovery and did not induce any relapse of hepatitis. This observation shows that clotiazepam can induce acute hepatitis and suggests that there is no cross hepatotoxicity between clotiazepam and several benzodiazepines. PMID:2572625

  2. Diffusion-induced Ramsey narrowing

    E-print Network

    Yanhong Xiao; Irina Novikova; David F. Phillips; Ronald L. Walsworth

    2005-07-19

    A novel form of Ramsey narrowing is identified and characterized. For long-lived coherent atomic states coupled by laser fields, the diffusion of atoms in-and-out of the laser beam induces a spectral narrowing of the atomic resonance lineshape. Illustrative experiments and an intuitive analytical model are presented for this diffusion-induced Ramsey narrowing, which occurs commonly in optically-interrogated systems.

  3. [Contrast-induced nephropathy].

    PubMed

    Santos, Ricardo Oliveira; Malvar, Beatriz; Silva, Rui; Ramalho, Vítor; Pessegueiro, Pedro; Amoedo, Manuel; Aniceto, João; Pires, Carlos

    2011-01-01

    Contrast-induced nephropathy (CIN) is an iatrogenic disorder, resulting from procedures requiring the intravascular administration of iodinated contrast media. It has an association with increased morbidity and mortality, increased costs and it remains the third most common cause of hospital-acquired kidney failure. CIN is usually defined as an increase in serum creatinine by either at least 0.5 mg/dl or by 25% from baseline within the first 48 hours after contrast administration, in the absence of other causes of renal function impairment. In its pathogenesis have been implicated 2 main mechanisms: renal vasoconstriction resulting in medullary hypoxia and direct cytotoxic effects of the contrast agents. There are several risk factors for radiocontrast nephrotoxicity but patients with underlying renal insufficiency or diabetic nephropathy with renal insufficiency have the greatest risk. Other classic risk factors include: advanced age, peri-procedural intravascular depletion, congestive heart failure. Finally, toxicity also depends on the volume, type of contrast administered and concomitant use of other nephrotoxic drugs. Since there is no specific treatment for CIN and it is limited to supportive measures, prevention is the best way to deal with this condition. In this setting it is important to use lower doses of a low or iso-osmolal agent and avoid volume depletion. Nowadays it is recommended to do volume expansion prior to and continued for several hours after the procedure. Randomized controlled trials suggest that isotonic intravenous fluids, particularly isotonic bicarbonate, confer better protection. Several pharmacologic approaches have been tested to decrease the risk of CIN in patients with preexisting renal disease, based in the mechanisms by which contrast medium is believed to cause nephrotoxicity. However, with the exception of some antioxidant agents, few of those adjunctive therapies have shown any consistent benefit. N-Acetylcysteine is the most widely studied of all prophylactic strategies and despite conflicting data it is advised to do an elevated dosage orally twice daily, the day before and the day of the procedure, based upon its potential for benefit, low toxicity and cost. This article pretends to review CIN pathogenesis, risk factors, clinical course, treatment and prevention. The authors propose themselves a prevention protocol for risk patients based on the latest clinical evidence. PMID:22525634

  4. Systemic resistance induced by rhizosphere bacteria

    Microsoft Academic Search

    L. C. van Loon; P. A. H. M. Bakker; C. M. J. Pieterse

    1998-01-01

    Nonpathogenic rhizobacteria can induce a systemic resistance in plants that is phenotypically similar to pathogen-induced systemic acquired resistance (SAR). Rhizobacteria-mediated induced systemic resistance (ISR) has been demonstrated against fungi, bacteria, and viruses in Arabidopsis, bean, carnation, cucumber, radish, tobacco, and tomato under conditions in which the inducing bacteria and the challenging pathogen remained spatially separated. Bacterial strains differ in their

  5. Water testing of the inducer pump. [LMFBR

    Microsoft Academic Search

    C. Dunn; R. K. Hoshide

    1977-01-01

    The inducer pump, designed and fabricated as a test article to evaluate the inducer\\/impeller pump concept for providing improved suction performance of large sodium pumps, met or exceeded all performance goals. The inducer stage in front of the centrifugal impeller dramatically reduces the size of pumps. It was demonstrated that the inducer can operate at suction specific speeds in excess

  6. PIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitro

    PubMed Central

    2011-01-01

    Background High-risk human papillomavirus (hrHPV) infections are causally related to cervical cancer development. The additional (epi)genetic alterations driving malignant transformation of hrHPV-infected cells however, are not yet fully elucidated. In this study we experimentally assessed the role of the PI3-kinase pathway and its regulator PIK3CA, which is frequently altered in cervical cancer, in HPV-induced transformation. Methods Cervical carcinomas and ectocervical controls were assessed for PIK3CA mRNA and protein expression by quantitative RT-PCR and immunohistochemical staining, respectively. A longitudinal in vitro model system of hrHPV-transfected keratinocytes, representing the immortal and anchorage independent phenotype, was assayed for PI3-kinase activation and function using chemical pathway inhibition i.e. LY294002 treatment, and PIK3CA RNA interference. Phenotypes examined included cellular viability, migration, anchorage independent growth and differentiation. mRNA expression of hTERT and HPV16 E6E7 were studied using quantitative RT-PCR and Northern blotting. Results Cervical carcinomas showed significant overexpression of PIK3CA compared to controls. During HPV-induced transformation in vitro, expression of the catalytic subunit PIK3CA as well as activation of downstream effector PKB/AKT progressively increased in parallel. Inhibition of PI3-kinase signalling in HPV16-transfected keratinocytes by chemical interference or siRNA-mediated silencing of PIK3CA resulted in a decreased phosphorylation of PKB/AKT. Moreover, blockage of PI3-kinase resulted in reduced cellular viability, migration, and anchorage independent growth. These properties were accompanied with a downregulation of HPV16E7 and hTERT mRNA expression. In organotypic raft cultures of HPV16- and HPV18-immortalized cells, phosphorylated PKB/AKT was primarily seen in differentiated cells staining positive for cytokeratin 10 (CK10). Upon PI3-kinase signalling inhibition, there was a severe impairment in epithelial tissue development as well as a dramatic reduction in p-PKB/AKT and CK10. Conclusion The present data indicate that activation of the PI3-kinase/PKB/AKT pathway through PIK3CA regulates various transformed phenotypes as well as growth and differentiation of HPV-immortalized cells and may therefore play a pivotal role in HPV-induced carcinogenesis. PMID:21663621

  7. Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection

    Microsoft Academic Search

    Z N Demidenko; C Vivo; H D Halicka; C J Li; K Bhalla; E V Broude; M V Blagosklonny

    2006-01-01

    Selective modulation of cell death is important for rational chemotherapy. By depleting Hsp90-client oncoproteins, geldanamycin (GA) and 17-allylamino-17-demethoxy-GA (17-AAG) (heat-shock protein-90-active drugs) render certain oncoprotein-addictive cancer cells sensitive to chemotherapy. Here we investigated effects of GA and 17-AAG in apoptosis-prone cells such as HL60 and U937. In these cells, doxorubicin (DOX) caused rapid apoptsis, whereas GA-induced heat-shock protein-70 (Hsp70) (a

  8. Late Onset Clozapine Induced Agranulocytosis

    PubMed Central

    Velayudhan, Rajmohan; Kakkan, Sushil

    2014-01-01

    Agranulocytosis is defined as an absolute neutrophil count less than 100/mm3 in association with infectious disease. The risk of agranulocytosis is 0.38% of all clozapine treated cases and there is a relatively lesser incidence in Indian population. The risk of clozapine-induced agranulocytosis and neutropenia is highest in the first 6 months and higher in the initial 18 months after the onset of treatment. There have been very few reports of neutropenia and agranulocytosis after this period. There have so far been no reports of late onset clozapine induced agranulocytosis has been reported from India. A case of late onset clozapine induced agranulocytosis with possible mechanism of the same is reported. PMID:25336778

  9. Persistent nicorandil induced oral ulceration

    PubMed Central

    Healy, C M; Smyth, Y; Flint, S R

    2004-01-01

    Four patients with nicorandil induced ulceration are described, and the literature on the subject is reviewed. Nicorandil induced ulcers are very painful and distressing for patients. Clinically they appear as large, deep, persistent ulcers that have punched out edges. They are poorly responsive to topical steroids and usually require alteration of nicorandil treatment. The ulceration tends to occur at high doses of nicorandil and all four cases reported here were on doses of 40 mg per day or greater. In these situations reduction of nicorandil dose may be sufficient to promote ulcer healing and prevent further recurrence. However, nicorandil induced ulcers have been reported at doses as low as 10 mg daily and complete cessation of nicorandil may be required. PMID:15201264

  10. Switching-induced Turing instability.

    PubMed

    Buceta, J; Lindenberg, Katja

    2002-10-01

    We propose a mechanism for inducing a Turing instability in systems whose only stable state is pattern-free and homogeneous. Global alternation between two dynamics, each of which has the same homogeneous stable state, may induce a Turing instability that leads to pattern formation. We determine what kind of alternation can drive the system to a Turing instability, and show that the appearance of the induced spatiotemporal structure depends on the ratio of two characteristic times, one determined by the external forcing and the other by the instability that drives the system at short times. The mechanism is illustrated by means of theoretical calculations and numerical simulations on two well-known biological models that are relevant in morphogenesis. PMID:12443294

  11. Induced abortion and contraception use

    PubMed Central

    du Prey, Beatrice; Talavlikar, Rachel; Mangat, Rupinder; Freiheit, Elizabeth A.; Drummond, Neil

    2014-01-01

    Abstract Objective To determine what proportion of women seeking induced abortion in the Calgary census metropolitan area were immigrants. Design For 2 months, eligible women were asked to complete a questionnaire. Women who refused were asked to provide their country of birth (COB) to assess for selection bias. Setting Two abortion clinics in Calgary, Alta. Participants Women presenting at or less than 15 weeks’ gestational age for induced abortion for maternal indications. Main outcome measures The primary outcome was the proportion of women seeking induced abortion services who were immigrants. Secondary outcomes compared socioeconomic characteristics and contraception use between immigrant and Canadian-born women. Results A total of 752 women either completed a questionnaire (78.6%) or provided their COB (21.4%). Overall, 28.9% of women living in the Calgary census metropolitan area who completed the questionnaire were immigrants, less than the 31.2% background proportion of immigrant women of childbearing age. However, 46.0% of women who provided only COB were immigrants. When these data were combined, 34.2% of women presenting for induced abortion identified as immigrant, a proportion not significantly different from the background proportion (P = .127). Immigrant women presenting for induced abortion tended to be older, more educated, married with children, and have increased parity. They were similar to Canadian-born women in number of previous abortions, income status, and employment status. Conclusion This study suggests that immigrant women in Calgary are not presenting for induced abortion in disproportionately higher numbers, which differs from existing European literature. This is likely owing to differing socioeconomic characteristics among the immigrant women in our study from what have been previously described in the literature (typically lower socioeconomic status). Much still needs to be explored with regard to factors influencing the use of abortion services by immigrant women. PMID:25217694

  12. Graphene with geometrically induced vorticity

    E-print Network

    Jiannis K. Pachos; Michael Stone; Kristan Temme

    2008-03-26

    At half filling, the electronic structure of graphene can be modelled by a pair of free two-dimensional Dirac fermions. We explicitly demonstrate that in the presence of a geometrically induced gauge field, an everywhere-real Kekule modulation of the hopping matrix elements can correspond to a non-real Higgs field with non-trivial vorticity. This provides a natural setting for fractionally charged vortices with localized zero modes. For fullerene-like molecules we employ the index theorem to demonstrate the existence of six low-lying states that do not depend strongly on the Kekule-induced mass gap.

  13. Iron Pill–Induced Gastritis

    PubMed Central

    Proksell, Siobhan; Kuan, Shih-Fan; Behari, Jaideep

    2013-01-01

    Iron-deficiency anemia is a prevalent condition treated with iron supplementation. Iron pill–induced gastritis is an under-recognized, albeit serious potential complication of iron pill ingestion. This entity must be identified by healthcare providers who prescribe iron. We present a case of a 59-year-old male with iron deficiency anemia on ferrous sulfate tablets who underwent an upper endoscopy, during which a single superficial gastric ulceration in the body was noted. Biopsies revealed heavy iron deposition confirming the ulceration was a consequence of the iron tablets. Iron pill–induced gastritis causes corrosive mucosal injury similar to that caused by chemical burns.

  14. Anaphylaxis induced by lentil inhalation.

    PubMed

    Ay?enur, Kaya; Akan, Ay?egül; Mustafa, Erkoço?lu; Müge, Toyran; Kocaba?, Can Naci

    2012-06-01

    Anaphylaxis is a rapid onset serious allergic reaction which may be fatal. Foods are the most common allergens leading to anaphylaxis especially for childhood. Most of the food-induced anaphylactic reactions take place after ingestion of the allergic food and only a few cases exist with anaphylactic reactions induced by inhalation of foods such as peanut, soybean and lupine. The case we present is unusual in that an 8 1/2-year-old boy developed anaphylaxis with the inhalation of steam from boiling lentils. PMID:22830298

  15. Mesna-induced photodistributed dermatosis.

    PubMed

    Lin, C Y; Keefe, M

    2012-06-01

    We present the case of a 41-year-old man who developed a photodistributed eruption 1 month after being started on 2-mercaptoethane sulfonate sodium (mesna) for treatment of cyclophosphamide-induced haemorrhagic cystitis. The patient had a background history of Wegener granulomatosis, and had been taking cyclophosphamide at a stable dose of 150 mg daily for the previous 3 years. Complete resolution of the rash occurred within 8 weeks of cessation of mesna. This is the first reported case, to our knowledge, of mesna-induced photodistributed dermatosis. Early recognition of this condition will ensure prompt cessation of the culprit medication, and consideration of alternative management of haemorrhagic cystitis. PMID:22103595

  16. BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

    Microsoft Academic Search

    John M. Goldman; Junia V. Melo

    2008-01-01

    The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce

  17. Cyclopamine-induced holoprosencephaly and associated craniofacial malformations in the golden hamster: anatomic and molecular events.

    PubMed

    Coventry, S; Kapur, R P; Siebert, J R

    1998-01-01

    Holoprosencephaly is a complex congenital malformation of the brain and is often associated with a spectrum of facial anomalies ranging from normocephaly or nondiagnostic changes to cleft lip/palate (premaxillary dysgenesis), cebocephaly, ethmocephaly, and cyclopia. The primary insult is thought to occur during gastrulation, when prechordal mesenchyme and overlying anterior neural plate undergo complex developmental interactions. Exposure to cyclopamine, a steroid isolated from the desert plant Veratrum californicum, causes holoprosencephaly in mammalian embryos. We have begun to study the pathogenesis of cyclopamine-induced holoprosencephaly and associated craniofacial anomalies in Syrian golden hamsters (Mesocricetus auratus). Embryos were exposed to a single maternal dose of cyclopamine during gastrulation on embryonic day (E) 7.0. By E13.0, 62% of fetuses showed craniofacial malformations, including premaxillary dysgenesis, ocular hypotelorism, and cebocephaly. Facial anomalies were associated with absence of the premaxilla and abnormalities of the midline cranial base, particularly the ethmoid and sphenoid bones. Histological sections from cyclopamine-treated embryos at earlier stages showed marked deficiency of cranial mesenchyme derived from the rostral neural crest. Expression of two transcription factors, HNF-3 beta and Hox-b5, which have been implicated in specification of rostral and caudal neural crest cells, respectively, were examined immunohistochemically. Treatment with cyclopamine caused a transient loss of HNF-3 beta immunoreactivity in prechordal mesenchyme, but had no effect on Hox-b5 expression. The findings suggest that an early event in the pathogenesis of cyclopamine-induced holoprosencephaly may be altered expression of selected proteins in the prechordal mesenchyme and floor plate with secondary impaired development of the adjacent neural plate and cranial neural crest. PMID:10463269

  18. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

    Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

  19. Electric field induced phase separation

    Microsoft Academic Search

    Ludwik Leibler

    2004-01-01

    In principle, magnetic and electric fields or gravity can control phase separation in liquid mixtures, but the coupling between these fields and the local concentration fluctuations is very weak and thus their use to control demixing seems limited to extreme conditions. Uniform electric fields induce detectable effects only very close to the transition temperature, at about few hundredths of degree

  20. Molecular Cell Hydroxyurea Induces Hydroxyl

    E-print Network

    Collins, James J.

    induces a set of protective responses to manage genomic instability. Continued HU stress activates iron superoxide production, together with the increased iron uptake, fuels the formation of hydroxyl radicals Escheri- chia coli, yeast, and humans (Rosenkranz et al., 1967; Sinha and Snustad, 1972). Several lines

  1. Methotrexate-Induced Liver Cirrhosis

    Microsoft Academic Search

    H. Zachariae; H. Søgaard

    1987-01-01

    Studies on serial liver biopsies from 25 patients with methotrexate-induced liver cirrhosis, taken from 1 to 13 years after cirrhosis was established, confirm that this type is not of aggressive nature. When evaluated blind no progression was found in most of the later biopsies. Alcohol and previous use of hepatotoxic drugs such as the combination of arsenics and vitamin A

  2. Nodal bradycardia induced by tocainide.

    PubMed Central

    Mandal, S. K.; Datta, S. K.

    1983-01-01

    A case of tocainide-induced nodal bradycardia in standard recommended dose is reported. There was no recurrence when the drug was subsequently reintroduced in a reduced dosage. It is suggested that in the elderly, tocainide should be used in a lower dosage than normally recommended. PMID:6408628

  3. UV-induced skin damage

    Microsoft Academic Search

    M. Ichihashi; M. Ueda; A. Budiyanto; T. Bito; M. Oka; M. Fukunaga; K. Tsuru; T. Horikawa

    2003-01-01

    Solar radiation induces acute and chronic reactions in human and animal skin. Chronic repeated exposures are the primary cause of benign and malignant skin tumors, including malignant melanoma. Among types of solar radiation, ultraviolet B (290–320 nm) radiation is highly mutagenic and carcinogenic in animal experiments compared to ultraviolet A (320–400 nm) radiation. Epidemiological studies suggest that solar UV radiation

  4. Antiviral drug-induced nephrotoxicity.

    PubMed

    Izzedine, Hassane; Launay-Vacher, Vincent; Deray, Gilbert

    2005-05-01

    Drug-induced kidney injury is a major side effect in clinical practice, frequently leading to acute renal failure (ARF). It accounts for more than 2% to 15% of cases of ARF in patients admitted to the hospital or in the intensive care unit, respectively. The exact frequency of nephrotoxicity induced by antiviral drugs is difficult to determine. Antiviral drugs cause renal failure through a variety of mechanisms. Direct renal tubular toxicity has been described with a number of new medications with unique effects on epithelial cells of the kidney. These include cidofovir, adefovir dipivoxil, and tenofovir, as well as acyclovir. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including acyclovir and the protease inhibitor indinavir. Renal injury associated with antiviral drugs involves diverse processes having effects on the renal transporters, as well as on tubule cells. In this article, we review the pathogenesis of antiviral drug-induced kidney injury, common nephrotoxic renal syndromes, and strategies for preventing kidney injury. PMID:15861345

  5. Adolescents and Exercise Induced Asthma

    ERIC Educational Resources Information Center

    Hansen, Pamela; Bickanse, Shanna; Bogenreif, Mike; VanSickle, Kyle

    2008-01-01

    This article defines asthma and exercise induced asthma, and provides information on the triggers, signs, and symptoms of an attack. It also gives treatments for these conditions, along with prevention guidelines on how to handle an attack in the classroom or on the practice field. (Contains 2 tables and 1 figure.)

  6. Managing Morphine-Induced Constipation

    Microsoft Academic Search

    P. R Ramesh; K. Suresh Kumar; M. R Rajagopal; P Balachandran; P. K Warrier

    1998-01-01

    Constipation is a frequent cause of distress in advanced cancer. A palliative care unit in Kerala, a southern state of India, conducted a controlled trial comparing a liquid Ayurvedic (herbal) preparation (Misrakasneham) with a conventional laxative tablet (Sofsena) in the management of opioid-induced constipation in patients with advanced cancer. Although there was no statistically significant difference in the apparent degree

  7. Flow-induced vibration: 1992

    Microsoft Academic Search

    1992-01-01

    A joint program on flow-induced vibration (FIV) as established in July 1988 between Taiwan Power Company (Taipower or TPC) and ANL. The main objectives of the program are to provide a technology transfer program on FIV for Taipower staff and to assist Taipower with various aspects of FIV including evaluation of reports and proposals, review of designs, resolution of design

  8. Acetaminophen-Induced Hepatic Necrosis

    Microsoft Academic Search

    D. J. Jollow; S. S. Thorgeirsson; W. Z. Potter; M. Hashimoto; J. R. Mitchell

    1974-01-01

    The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low doses of acetaminophen converted to the mercapturic acid metabolite was highest in the most susceptible species (hamsters, mice), and lowest in the more resistant species (rat). Pretreatment regimens known to potentiate the hepatotoxicity

  9. Electromagnetically induced photonic band gap

    Microsoft Academic Search

    Yuri V. Rostovtsev; Andrey B. Matsko; Marlan O. Scully

    1999-01-01

    A nonlinear propagation of electromagnetic waves has been investigated in a heterostructure formed by spatially modulated density of ladder-type (Xi) three-level atoms. The appearance of a forbidden band gap for an electromagnetic field induced by another electromagnetic field has been found. An alternative concept of an optical transistorlike device based on this effect has been proposed.

  10. Grinding induced damage in ceramics

    Microsoft Academic Search

    Bi Zhang; X. L Zheng; H Tokura; M Yoshikawa

    2003-01-01

    Although grinding is widely used as a productive technique for finishing ceramic components in the manufacturing industry, it often causes damage to the machined components. The exact nature, the manner and the penetration depth of grinding-induced damage are, however, still not clear, leaving many uncertainties and sometimes danger in using ceramics for structural applications. This paper presents research results on

  11. Noise-induced spatial patterns

    Microsoft Academic Search

    Juan M. R. Parrondo; Christian van den Broeck; Javier Buceta; F. Javier de la Rubia

    1996-01-01

    By modifying the spatial coupling a la Swift-Hohenberg in the model introduced in Phys. Rev. Lett. 73 (1994) 3395, we obtain a system that displays noise-induced spatial patterns. We present a mean field theory of this phenomenon and verify some of its predictions by numerical simulations.

  12. An inducible offense: carnivore morph tadpoles induced by tadpole carnivory

    PubMed Central

    Levis, Nicholas A; de la Serna Buzón, Sofia; Pfennig, David W

    2015-01-01

    Phenotypic plasticity is commonplace, and plasticity theory predicts that organisms should often evolve mechanisms to detect and respond to environmental cues that accurately predict future environmental conditions. Here, we test this prediction in tadpoles of spadefoot toads, Spea multiplicata. These tadpoles develop into either an omnivore ecomorph, which is a dietary generalist, or a carnivore ecomorph, which specializes on anostracan shrimp and other tadpoles. We investigated a novel proximate cue – ingestion of Scaphiopus tadpoles – and its propensity to produce carnivores by rearing tadpoles on different diets. We found that diets containing tadpoles from the genus Scaphiopus produced more carnivores than diets without Scaphiopus tadpoles. We discuss why Scaphiopus tadpoles are an excellent food source and why it is therefore advantageous for S. multiplicata tadpoles to produce an inducible offense that allows them to better utilize this resource. In general, such inducible offenses provide an excellent setting for investigating the proximate and evolutionary basis of phenotypic plasticity. PMID:25897380

  13. Cancellation of Crosstalk-Induced Jitter

    Microsoft Academic Search

    James F. Buckwalter; Ali Hajimiri

    2006-01-01

    Abstract—A novel jitter equalization circuit is presented that addresses crosstalk-induced jitter in high-speed serial links. A simple model of electromagnetic coupling demonstrates the generation of crosstalk-induced jitter. The analysis highlights unique aspects of crosstalk-induced jitter that differ from far-end crosstalk. The model is used to predict the crosstalk-induced jitter in 2-PAM and 4-PAM, which is compared to measurement. Furthermore, the

  14. Irradiation-induced phenomena in carbon

    E-print Network

    Krasheninnikov, Arkady V.

    Chapter 1 Irradiation-induced phenomena in carbon nanotubes To appear in "Chemistry of Carbon@acclab.helsinki.fi 1 #12;2CHAPTER 1. IRRADIATION-INDUCED PHENOMENA IN CARBON NANOTUBES #12;Contents 1 Irradiation-induced phenomena in carbon nanotubes 1 1.1 Introduction

  15. Swept Inducer Blades With Tandem Radial Slots

    NASA Technical Reports Server (NTRS)

    Meng, Sen Y.

    1995-01-01

    Slanted radial slots at tandem positions along approximate streamlines incorporated into swept inducer blades in turbopump, according to proposal. With suitable design, slots suppress low-frequency oscillations induced by cavitation, without causing excessive loss of inducer head. Slots cut into solid blades by wire electrical-discharge machining.

  16. Dose-dependent olanzapine-induced myoclonus.

    PubMed

    Tikka, Sai Krishna; Pratap, Alok; Sinha, Vinod Kumar

    2014-01-01

    Second-generation antipsychotics (SGA), mainly clozapine have been reported to induce myoclonus. Although olanzapine-induced myoclonus is reported, dose-dependent response has not been described. We report dose-related olanzapine-induced myoclonus in an early onset schizophrenia patient. We also suggest certain management strategies for such adverse side effects. PMID:25948979

  17. Noise induced hearing loss in children; a \\

    Microsoft Academic Search

    Robert V. Harrison

    A review of the problems of noise induced hearing loss in children, especially related to recreational music and the use of personal entertainment devices. The patho-physiology of noise induced hearing loss, and associated problems (e.g. tinnitus) are discussed. The evidence for an increase in noise induced hearing loss in children and young people is reviewed. Some practical advice (for clinicians,

  18. Exercise training reverses age-induced inducible nitric oxide synthase upregulation 

    E-print Network

    Song, Wook

    2005-02-17

    EXERCISE TRAINING REVERSES AGE-INDUCED INDUCIBLE NITRIC OXIDE SYNTHASE UPREGULATION A Dissertation by WOOK SONG Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment... of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2003 Major Subject: Kinesiology EXERCISE TRAINING REVERSES AGE-INDUCED INDUCIBLE NITRIC OXIDE SYNTHASE UPREGULATION A Dissertation by WOOK SONG...

  19. Dipole-Induced Electromagnetic Transparency

    E-print Network

    Raiju Puthumpally-Joseph; Maxim Sukharev; Osman Atabek; Eric Charron

    2014-09-22

    We determine the optical response of a thin and dense layer of interacting quantum emitters. We show that in such a dense system, the Lorentz redshift and the associated interaction broadening can be used to control the transmission and reflection spectra. In the presence of overlapping resonances, a Dipole-Induced Electromagnetic Transparency (DIET) regime, similar to Electromagnetically Induced Transparency (EIT), may be achieved. DIET relies on destructive interference between the electromagnetic waves emitted by quantum emitters. Carefully tuning material parameters allows to achieve narrow transmission windows in otherwise completely opaque media. We analyze in details this coherent and collective effect using a generalized Lorentz model and show how it can be controlled. Several potential applications of the phenomenon, such as slow light, are proposed.

  20. Drug-induced hepatic steatosis.

    PubMed

    Amacher, David E; Chalasani, Naga

    2014-05-01

    Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS. PMID:24879984

  1. Methadone Induced Sensorineural Hearing Loss

    PubMed Central

    Saifan, Chadi; Barakat, Iskandar; El-Sayegh, Suzanne

    2013-01-01

    Background. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL. PMID:23983704

  2. Gyromagnetically induced transparency of metasurfaces.

    PubMed

    Mousavi, S Hossein; Khanikaev, Alexander B; Allen, Jeffery; Allen, Monica; Shvets, Gennady

    2014-03-21

    We demonstrate that the presence of a (gyro) magnetic substrate can produce an analog of electromagnetically induced transparency in Fano-resonant metamolecules. The simplest implementation of such gyromagnetically induced transparency (GIT) in a metasurface, comprised of an array of resonant antenna pairs placed on a gyromagnetic substrate and illuminated by a normally incident electromagnetic wave, is analyzed. Time reversal and spatial inversion symmetry breaking introduced by the dc magnetization makes metamolecules bianisotropic. This causes Fano interference between the otherwise uncoupled symmetric and antisymmetric resonances of the metamolecules giving rise to a sharp transmission peak through the otherwise reflective metasurface. We show that, for an oblique wave incidence, one-way GIT can be achieved by the combination of spatial dispersion and gyromagnetic effect. These theoretically predicted phenomena pave the way to nonreciprocal switches and isolators that can be dynamically controlled by electric currents. PMID:24702414

  3. Valproate-induced hyperammonemic encephalopathy.

    PubMed

    Chou, Hsiao-Feng; Yang, Rei-Cheng; Chen, Cheng Ying; Jong, Yuh-Jyh

    2008-10-01

    Valproate-induced hyperammonemic encephalopathy is an unusual but serious complication that can occur in people with normal liver-associated enzyme levels, and despite normal therapeutic doses and serum levels of valproate. Here, we describe an adolescent girl suffering from absence seizures, who complained of progressive dizziness and general malaise several days after restarting valproate. She developed vomiting and decreased consciousness after 3 weeks of valproate use. She had a serum ammonia level five times higher than the upper normal limit, normal liver-associated enzymes, and a supra-therapeutic valproate level. Electroencephalography (EEG) showed continuous generalized slowing. Tandem mass spectrometry analysis revealed carnitine deficiency. Her consciousness improved after emergent hemodialysis. Her ammonia level and EEG also became normal. Possible mechanisms, risk factors and treatments of valproate-induced hyperammonemic encephalopathy are described. Physicians should consider this possibility when consciousness disturbance occurs in patients treated with valproate. PMID:19133574

  4. Molecular mechanisms of induced pluripotency.

    PubMed

    Kulcenty, Katarzyna; Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa; Jaworski, Jacek

    2015-01-01

    Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types. PMID:25691818

  5. Drug-induced Liver Injury

    PubMed Central

    David, Stefan; Hamilton, James P

    2011-01-01

    Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. PMID:21874146

  6. Aloe-induced Toxic Hepatitis

    PubMed Central

    Yang, Ha Na; Kim, Young Mook; Kim, Byoung Ho; Sohn, Kyoung Min; Choi, Myung Jin; Choi, Young Hee

    2010-01-01

    Aloe has been widely used in phytomedicine. Phytomedicine describes aloe as a herb which has anti-inflammatory, anti-proliferative, anti-aging effects. In recent years several cases of aloe-induced hepatotoxicity were reported. But its pharmacokinetics and toxicity are poorly described in the literature. Here we report three cases with aloe-induced toxic hepatitis. A 57-yr-old woman, a 62-yr-old woman and a 55-yr-old woman were admitted to the hospital for acute hepatitis. They had taken aloe preparation for months. Their clinical manifestation, laboratory findings and histologic findings met diagnostic criteria (RUCAM scale) of toxic hepatitis. Upon discontinuation of the oral aloe preparations, liver enzymes returned to normal level. Aloe should be considered as a causative agent in hepatotoxicity. PMID:20191055

  7. [Drug-induced lung diseases].

    PubMed

    Medici, T C; Fontana, A

    1977-02-12

    Adverse drug reactions involving different organs, including the lung, are numerous; much more numerous, however, are the offending drugs. According to the results of the Boston Collaborative Drug Surveillance Program, adverse reactions occur in about 6% of all drug exposures and 28% of all patients. Drug-induced lung diseases may present as bronchial reactions (e.g. bronchial asthma), diseases of the parenchyma (e.g. pulmonary infiltrates with eosinophilia, diffuse fibrosing alveolitis), of the pulmonary vasculature (vasculitis) and of the pleura (e.g. pleurisy or pleural fibrosis). Pathogenetically the two most pertinent types of reaction are hypersensitivity or toxic reactions, and less often biologic reactions such as opportunistic infections after cytotoxic and immunosuppressive therapy. Many drug-induced respiratory diseases are reversible upon withdrawal of the offending agent; others may be irreversibly or even progress. PMID:13491

  8. Molecular mechanisms of induced pluripotency

    PubMed Central

    Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa

    2015-01-01

    Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types. PMID:25691818

  9. Enoxaparin-Induced DRESS Syndrome

    PubMed Central

    Ronceray, Sophie; Dinulescu, Monica; Le Gall, François; Polard, Elisabeth; Dupuy, Alain; Adamski, Henri

    2012-01-01

    Low-molecular-weight heparins are widely used for the prophylaxis and treatment of venous thromboembolism. However, they can induce adverse skin reactions. The most common reactions are delayed-type hypersensitivity reactions at injection sites. Rare systemic reactions have been reported. We report, to our knowledge, the first case of a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) due to enoxaparin which belongs to the low-molecular-weight heparins class. PMID:23185158

  10. Laser-Induced Thermal Acoustics

    Microsoft Academic Search

    Eric Bryant Cummings

    1995-01-01

    Laser-induced thermal acoustics (LITA) is a new technique for remote nonintrusive measurement of thermophysical gas properties. LITA involves forming, via opto-acoustic effects, grating-shaped perturbations of gas properties by the use of intersecting beams from a short-pulse laser. A third beam scatters coherently into a signal beam off the perturbation grating via acousto-optical effects. The evolution of the gas perturbations modulates

  11. Medication-induced peripheral neuropathy

    Microsoft Academic Search

    Louis H. Weimer

    2003-01-01

    Although not very common, medication-induced neuropathy is a treatable condition and, therefore, is important to identify.\\u000a Medications continue to grow in number and expand in usage; consequently, toxic neuropathy continues to be relevant to neurologists.\\u000a Many agents have toxicities that are tolerated because the treatments are necessary, such as therapies for HIV and malignancy.\\u000a Additional agents to prevent or ameliorate

  12. Ellipticity induced in vacuum birefringence

    E-print Network

    Greger Torgrimsson

    2014-09-29

    We consider signals of photon-photon scattering in laser-based, low energy experiments. In particular, we consider the ellipticity induced on a probe beam by a strong background field, and compare it with a recent worldline expression for the photon polarisation flip amplitude. When the probe and the background are plane waves, the ellipticity is equal to the flip amplitude. Here we investigate the ellipticity-amplitude relation for more physical fields.

  13. Ellipticity induced in vacuum birefringence

    E-print Network

    Torgrimsson, Greger

    2014-01-01

    We consider signals of photon-photon scattering in laser-based, low energy experiments. In particular, we consider the ellipticity induced on a probe beam by a strong background field, and compare it with a recent worldline expression for the photon polarisation flip amplitude. When the probe and the background are plane waves, the ellipticity is equal to the flip amplitude. Here we investigate the ellipticity-amplitude relation for more physical fields.

  14. Severe amiodarone induced pulmonary toxicity

    PubMed Central

    Nacca, Nicholas; Yuhico, Luke S; Pinnamaneni, Sowmya; Szombathy, Tamas

    2012-01-01

    A known complication of Amiodarone therapy is Amiodarone induced Pulmonary Toxicity (APT). Several features of this adverse effect make it difficult to diagnosis and treat. The case of a 63-year-old male with classic radiographic and histologic findings of APT is discussed. Clinical presentation, pathophysiology, diagnostic findings, and treatment strategies are reviewed. The patient was successfully managed with pulse high dose steroid therapy. PMID:23205299

  15. Peanut–Induced Anaphylactic Reactions

    Microsoft Academic Search

    Wesley Burks; Gary A. Bannon; Scott Sicherer; Hugh A. Sampson

    1999-01-01

    Food allergies, particularly to peanuts, are a common cause of anaphylaxis. Approximately 125 people die each year in the USA secondary to food–induced anaphylaxis. Clinical anaphylaxis is a syndrome of diverse etiology and dramatic presentation of symptoms associated with the classic features of type I, IgE–mediated hypersensitivity [1]. Typically the term anaphylaxis connotes an immunologically–mediated event that occurs after exposure

  16. Acoustically-Induced Electrical Signals

    NASA Astrophysics Data System (ADS)

    Brown, S. R.

    2014-12-01

    We have observed electrical signals excited by and moving along with an acoustic pulse propagating in a sandstone sample. Using resonance we are now studying the characteristics of this acousto-electric signal and determining its origin and the controlling physical parameters. Four rock samples with a range of porosities, permeabilities, and mineralogies were chosen: Berea, Boise, and Colton sandstones and Austin Chalk. Pore water salinity was varied from deionized water to sea water. Ag-AgCl electrodes were attached to the sample and were interfaced to a 4-wire electrical resistivity system. Under computer control, the acoustic signals were excited and the electrical response was recorded. We see strong acoustically-induced electrical signals in all samples, with the magnitude of the effect for each rock getting stronger as we move from the 1st to the 3rd harmonics in resonance. Given a particular fluid salinity, each rock has its own distinct sensitivity in the induced electrical effect. For example at the 2nd harmonic, Berea Sandstone produces the largest electrical signal per acoustic power input even though Austin Chalk and Boise Sandstone tend to resonate with much larger amplitudes at the same harmonic. Two effects are potentially responsible for this acoustically-induced electrical response: one the co-seismic seismo-electric effect and the other a strain-induced resistivity change known as the acousto-electric effect. We have designed experimental tests to separate these mechanisms. The tests show that the seismo-electric effect is dominant in our studies. We note that these experiments are in a fluid viscosity dominated seismo-electric regime, leading to a simple interpretation of the signals where the electric potential developed is proportional to the local acceleration of the rock. Toward a test of this theory we have measured the local time-varying acoustic strain in our samples using a laser vibrometer.

  17. Volatile anesthetic-induced preconditioning.

    PubMed

    Swyers, T; Redford, D; Larson, D F

    2014-01-01

    The myocardium has an innate ability to protect itself from ischemic events. This protection occurs when the myocardium is exposed to a brief ischemic period prior to a more extreme ischemic event. This is termed ischemic preconditioning. Ischemic preconditioning induces a series of molecular pathways that protect the cardiac myocyte; first, for a period of 1-6 hours (early preconditioning) and, also, for a second period from 24-72 hours (delayed phase). The early preconditioning is mediated by the release of adenosine which induces a protective signal that is related to the mitochondrial KATP channel activation and activation of the ?-opioid and bradykinin receptors. The delayed phase is related to the induction of inducible nitric oxide synthase, superoxide dismutase and heat-shock proteins. Indirect evidence indicates that O2-derived free radicals are involved in the delayed phase, as noted in the early preconditioning phase. Applying ischemic preconditioning to clinical practice can be dangerous and difficult to implement in a controlled fashion. However, recent studies have shown that the use of volatile anesthetics, such as sevoflurane, isoflurane and desflurane, can mimic the early phase of ischemic preconditioning through a multi-pathway signaling of mitochondrial KATP channels. This important finding can easily be applied to clinical practice for patients undergoing surgery. It can also be significantly important for patients undergoing off-pump cardiac bypass surgery or cardiac bypass surgery where there is no cross-clamp or cardioplegia used where the probability of myocardial ischemia is greatly increased. This report will, therefore, discuss the mechanism, safety and efficacy of volatile anesthetics as inducers of cardiac preconditioning. PMID:24002781

  18. Drug-induced lupus erythematosus

    Microsoft Academic Search

    Camilla Dalle Vedove; Micol Del Giglio; Donatella Schena; Giampiero Girolomoni

    2009-01-01

    Drug-induced lupus erythematosus (DILE) is defined as a lupus-like syndrome temporally related to continuous drug exposure\\u000a which resolves after discontinuation of the offending drug. There are currently no standard diagnostic criteria for DILE and\\u000a the pathomechanisms are still unclear. Similarly to idiopathic lupus, DILE can be diveded into systemic (SLE), subacute cutaneous\\u000a (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE

  19. Drug-Induced Liver Injury.

    PubMed

    Fisher, Kurt; Vuppalanchi, Raj; Saxena, Romil

    2015-07-01

    Context .- Drug-induced liver injury (DILI) represents a diverse set of responses following exposure to any manufactured or naturally occurring chemical compound. Drug-induced liver injury is of major concern owing to the ever increasing number of compounds introduced into the market for treatment of various diseases as well as the increasing popularity of herbals, which lend themselves to self-medication but are not rigorously regulated. Objective .- To provide an overview of the prevalence, classification, and diagnosis of DILI with emphasis on pathogenesis and the role of a liver biopsy. To focus on the most common, emerging, and herbal agents that cause DILI with emphasis on the histologic pattern of injury observed. Data Sources .- A review of the literature was drawn from the PubMed (US National Library of Medicine) repository, textbooks, and online databases. All figures were taken from cases seen at our tertiary referral center, which is 1 of 12 participating sites in the National Institutes of Health-funded Drug-Induced Liver Injury Network. Conclusions .- Drug-induced liver injury due to prescription, over-the-counter, and herbal products is a major cause of liver disease in the United States and around the world. Diagnosis of DILI is challenging because there is no single clinical, laboratory, or histologic feature specific to DILI. Accurate diagnosis requires establishing a causal relationship with the suspected agent and excluding competing causes of liver injury. The liver biopsy is an essential component in the management of DILI by offering clues to the underlying pathogenesis, providing prognostic information, and guiding therapy. PMID:26125428

  20. Doubly diversity-induced resonance

    NASA Astrophysics Data System (ADS)

    Gassel, Martin; Glatt, Erik; Kaiser, Friedemann

    2007-07-01

    The influence of variability on the response of a net of bistable FitzHugh-Nagumo elements to a weak signal is investigated. The response of the net undergoes a resonancelike behavior due to additive variability. For an intermediate strength of additive variability the external signal is optimally enhanced in the output of the net (diversity-induced resonance). Furthermore, we show that additive noise strongly influences the diversity-induced resonance. Afterwards the interplay of additive and multiplicative variability on the response of the net is investigated. Starting with asymmetric bistable elements the enhancement of the signal is not very pronounced in the presence of additive variability. Via symmetry restoration by multiplicative variability the resonance is further enhanced. We call this phenomenon doubly diversity-induced resonance, because the interplay of both, additive and multiplicative variability, is essential to achieve the optimal enhancement of the signal. The restoration of symmetry can be explained by a systematic effect of the multiplicative variability, which changes the thresholds for the transitions between the two stable fixed points. We investigate the response to variability for globally and diffusively coupled networks and in dependency on the coupling strength.

  1. Field induced gap infrared detector

    NASA Technical Reports Server (NTRS)

    Elliott, C. Thomas (inventor)

    1990-01-01

    A tunable infrared detector which employs a vanishing band gap semimetal material provided with an induced band gap by a magnetic field to allow intrinsic semiconductor type infrared detection capabilities is disclosed. The semimetal material may thus operate as a semiconductor type detector with a wavelength sensitivity corresponding to the induced band gap in a preferred embodiment of a diode structure. Preferred semimetal materials include Hg(1-x)Cd(x)Te, x is less than 0.15, HgCdSe, BiSb, alpha-Sn, HgMgTe, HgMnTe, HgZnTe, HgMnSe, HgMgSe, and HgZnSe. The magnetic field induces a band gap in the semimetal material proportional to the strength of the magnetic field allowing tunable detection cutoff wavelengths. For an applied magnetic field from 5 to 10 tesla, the wavelength detection cutoff will be in the range of 20 to 50 micrometers for Hg(1-x)Cd(x)Te alloys with x about 0.15. A similar approach may also be employed to generate infrared energy in a desired band gap and then operating the structure in a light emitting diode or semiconductor laser type of configuration.

  2. Interferon treatment of human keratinocytes harboring extrachromosomal, persistent HPV-16 plasmid genomes induces de novo viral integration.

    PubMed

    Lace, Michael J; Anson, James R; Haugen, Thomas H; Dierdorff, Jason M; Turek, Lubomir P

    2015-01-01

    Interferons (IFNs) have been used to treat epithelial lesions caused by human papillomavirus (HPV) persistence. Here, we exposed primary human keratinocytes (HFKs) immortalized by persistently replicating HPV-16 plasmid genomes to increasing levels of IFN-?. While untreated HFKs retained replicating HPV-16 plasmids for up to 60-120 population doublings, IFN led to rapid HPV-16 plasmid loss. However, treated cultures eventually gave rise to outgrowth of clones harboring integrated HPV-16 genomes expressing viral E6 and E7 oncogenes from chimeric virus-cell mRNAs similar to those in cervical and head and neck cancers. Surprisingly, every HPV-16 integrant that arose after IFN exposure stemmed from an independent integration event into a different cellular gene locus, even within parallel cultures started from small cell inocula and cultured separately for ? 25 doublings to permit the rise and expansion of spontaneous integrants. While IFN treatment conferred a growth advantage upon preexisting integrants added to mixed control cultures, our results indicate that IFN exposure directly or indirectly induces HPV-16 integration, rather than only selects preexisting, spontaneous integrants that appear to be much less frequent. We estimate that IFN exposure increased integration rates by ? 100-fold. IFN-induced HPV-16 integration involved a wide range of chromosomal loci with less apparent selection for recurrent insertions near genes involved in cancer-related pathways. We conclude that IFNs and other potential treatments targeting high-risk HPV persistence that disrupt viral genome replication may promote increased high-risk HPV integration as a step in cancer progression. Therapies against high-risk HPV persistence thus need to be evaluated for their integration-inducing potential. PMID:25416558

  3. Ion beam induced luminescence: Relevance to radiation induced bystander effects

    NASA Astrophysics Data System (ADS)

    Ahmad, S. B.; McNeill, F. E.; Byun, S. H.; Prestwich, W. V.; Seymour, C.; Mothersill, C. E.

    2012-10-01

    The aim of this work is quantify the light emitted as a result of charged particle interaction in materials which may be of relevance to radiation induced "bystander effects" studies. We have developed a system which employs single photon counting to measure the light emitted from samples irradiated under vacuum by a charged particle beam. The system uses a fast photomultiplier tube with a peak cathode response at 420 nm. It has been tested in a proof-of-principle experiment using polystyrene targets. Light output, as a result of irradiation, was measured. The luminescence yield appears to have a non-linear behavior with the incident ion fluence: it rises exponentially to an asymptotic value. The target was irradiated with beam energies varying from 1 to 2 MeV and showed saturation at or before an incident fluence rate of 3 × 1013 H+/cm2 s. The average saturation value for the photon output was found to be 40 × 106 cps. Some measurements were performed using filters to study the emission at specific wavelengths. In the case of filtered light measurements, the photon output was found to saturate at 28 × 103, 10 × 106, and 35 × 106 cps for wavelengths of 280 ± 5 nm, 320 ± 5 nm and 340 ± 5 nm respectively. The light output reaches a maximum value because of damage induced in the polymer. Our measurements indicate a "damage cross section" of the order of 10-14 cm2. The average radiant intensity was found to increase at wavelengths of 280 and 320 nm when the proton energy was increased. This was not found to occur at 340 nm. In conclusion, the light emission at specific wavelengths was found to depend upon the incident proton fluence and the proton energy. The wavelengths of the emitted light measured in this study have significance for the understanding of radiation induced bystander effects.

  4. Drug-induced nail disorders.

    PubMed

    2014-07-01

    Nail disorders are defined according to their appearance and the part of the nail affected: the nail plate, the tissues that support or hold the nail plate in place, or the lunula. The consequences of most nail disorders are purely cosmetic. Other disorders, such as ingrown nails, inflammation, erythema, abscesses or tumours, cause functional impairment or pain. The appearance of the lesions is rarely indicative of their cause. Possible causes include physiological changes, local disorders or trauma, systemic conditions, toxic substances and drugs. Most drug-induced nail disorders resolve after discontinuation of the drug, although complete resolution sometimes takes several years. Drugs appear to induce nail disorders through a variety of mechanisms. Some drugs affect the nail matrix epithelium, the nail bed or the nail folds. Some alter nail colour. Other drugs induce photosensitivity. Yet others affect the blood supply to the nail unit. Nail abnormalities are common during treatment with certain cytotoxic drugs: taxanes, anthracyclines, fluorouracil, EGFR, tyrosine kinase inhibitors, etc. Some drugs are associated with a risk of serious and painful lesions, such as abscesses. When these disorders affect quality of life, the benefits of withdrawing the drug must be weighed against the severity of the condition being treated and the drug's efficacy, taking into account the harm-benefit balance of other options. Various anti-infective drugs, including tetracyclines, quinolones, clofazimine and zidovudine, cause the nail plate to detach from the nail bed after exposure to light, or cause nail discoloration. Psoralens and retinoids can also have the same effects. PMID:25162091

  5. Laser Induced Blue Luminescence Phenomenon

    NASA Astrophysics Data System (ADS)

    Zhu, Haiyong; Duan, Yanmin; Zhang, Ge; Zhang, Yaoju; Yang, Fugui

    2011-09-01

    Laser induced strange blue luminescence in several Raman crystals has been investigated. The blue luminescence at about 473 nm has the characteristic of no orientation and only produced in the crystal where the fundament laser oscillated. The experimental results show that the blue luminescence must result from the fundamental laser around 1.0 µm rather than Stokes-shifting. The spectrum detected is similar for different crystals. This blue luminescence is obviously strange and inconsistent with traditional luminescence theories, which maybe a brand-new luminescence theory.

  6. Molecular Control of Induced Pluripotency

    PubMed Central

    Theunissen, Thorold W.; Jaenisch, Rudolf

    2014-01-01

    Deciphering the mechanisms of epigenetic reprogramming provides fundamental insights into cell fate decisions, which in turn reveal strategies to make the reprogramming process increasingly efficient. Here we review recent advances in epigenetic reprogramming to pluripotency with a focus on the principal molecular regulators. We examine the molecular trajectories connecting somatic and pluripotent cells, genetic and chemical methodologies for inducing pluripotency, the role of endogenous master transcription factors in establishing the pluripotent state, and functional interactions between reprogramming factors and epigenetic regulators. Defining the cross-talk among the diverse molecular actors implicated in cellular reprogramming presents a major challenge for future inquiry. PMID:24905163

  7. Drug-induced esophageal strictures.

    PubMed Central

    Bonavina, L; DeMeester, T R; McChesney, L; Schwizer, W; Albertucci, M; Bailey, R T

    1987-01-01

    A retrospective study of 55 patients with a benign esophageal stricture showed that in 11 patients (20%) the cause was a drug-induced lesion due to potassium chloride (3), tetracyclines (3), aspirin (2), vitamin C (1), phenytoin (1), and quinidine (1). Five of the 11 patients would have been diagnosed as having a reflux etiology of their stricture if 24-hour esophageal pH monitoring was not performed. Six patients responded to dilatation and five patients required resection or bypass. A prospective study of 18 asymptomatic volunteers showed a high incidence of esophageal lodgment of a radiolabeled medicinal capsule, with subsequent dissolution and release of the isotope. This occurred most frequently in elderly subjects and was reduced by increasing the volume of water chaser. The sites of lodgment correspond to the location of the observed strictures in the patient population. An in vitro study showed that, when the causative drugs were mixed with saliva, dissolution occurred within 60 minutes and was associated with significant changes in pH. These investigations show that drug-induced esophageal strictures are more common than previously appreciated, and can be confused with a reflux etiology. Diagnosis is suggested by a history of drug ingestion, location of the stricture, and a normal esophageal acid exposure on 24-hour pH monitoring. The severity of the esophageal injury is variable and requires dilatation to resection for therapy. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:3606243

  8. Psychosocial aspects of induced abortion.

    PubMed

    Stotland, N L

    1997-09-01

    US anti-abortion groups have used misinformation on the long-term psychological impact of induced abortion to advance their position. This article reviews the available research evidence on the definition, history, cultural context, and emotional and psychiatric sequelae of induced abortion. Notable has been a confusion of normative, transient reactions to unintended pregnancy and abortion (e.g., guilt, depression, anxiety) with serious mental disorders. Studies of the psychiatric aspects of abortion have been limited by methodological problems such as the impossibility of randomly assigning women to study and control groups, resistance to follow-up, and confounding variables. Among the factors that may impact on an unintended pregnancy and the decision to abort are ongoing or past psychiatric illness, poverty, social chaos, youth and immaturity, abandonment issues, ongoing domestic responsibilities, rape and incest, domestic violence, religion, and contraceptive failure. Among the risk factors for postabortion psychosocial difficulties are previous or concurrent psychiatric illness, coercion to abort, genetic or medical indications, lack of social supports, ambivalence, and increasing length of gestation. Overall, the literature indicates that serious psychiatric illness is at least 8 times more common among postpartum than among postabortion women. Abortion center staff should acknowledge that the termination of a pregnancy may be experienced as a loss even when it is a voluntary choice. Referrals should be offered to women who show great emotional distress, have had several previous abortions, or request psychiatric consultation. PMID:9328746

  9. Simulations of Cavitating Cryogenic Inducers

    NASA Technical Reports Server (NTRS)

    Dorney, Dan (Technical Monitor); Hosangadi, Ashvin; Ahuja, Vineet; Ungewitter, Ronald J.

    2004-01-01

    Simulations of cavitating turbopump inducers at their design flow rate are presented. Results over a broad range of Nss, numbers extending from single-phase flow conditions through the critical head break down point are discussed. The flow characteristics and performance of a subscale geometry designed for water testing are compared with the fullscale configuration that employs LOX. In particular, thermal depression effects arising from cavitation in cryogenic fluids are identified and their impact on the suction performance of the inducer quantified. The simulations have been performed using the CRUNCH CFD[R] code that has a generalized multi-element unstructured framework suitable for turbomachinery applications. An advanced multi-phase formulation for cryogenic fluids that models temperature depression and real fluid property variations is employed. The formulation has been extensively validated for both liquid nitrogen and liquid hydrogen by simulating the experiments of Hord on hydrofoils; excellent estimates of the leading edge temperature and pressure depression were obtained while the comparisons in the cavity closure region were reasonable.

  10. Ion-induced nuclear radiotherapy

    DOEpatents

    Horn, K.M.; Doyle, B.L.

    1996-08-20

    Ion-induced Nuclear Radiotherapy (INRT) is a technique for conducting radiosurgery and radiotherapy with a very high degree of control over the spatial extent of the irradiated volume and the delivered dose. Based upon the concept that low energy, ion induced atomic and nuclear reactions can be used to produce highly energetic reaction products at the site of a tumor, the INRT technique is implemented through the use of a conduit-needle or tube which conducts a low energy ion beam to a position above or within the intended treatment area. At the end of the conduit-needle or tube is a specially fabricated target which, only when struck by the ion beam, acts as a source of energetic radiation products. The inherent limitations in the energy, and therefore range, of the resulting reaction products limits the spatial extent of irradiation to a pre-defined volume about the point of reaction. Furthermore, since no damage is done to tissue outside this irradiated volume, the delivered dose may be made arbitrarily large. INRT may be used both as a point-source of radiation at the site of a small tumor, or as a topical bath of radiation to broad areas of diseased tissue. 25 figs.

  11. Medication-induced oesophageal disorders.

    PubMed

    Petersen, Karl-Uwe; Jaspersen, Daniel

    2003-09-01

    Medication-induced oesophageal distress and injury have become increasingly common conditions. First, smooth muscle relaxants may worsen or produce symptoms of pre-existing gastro-oesophageal reflux disease; notable examples include certain calcium antagonists (nifedipine), nitrates, sildenafil, nicotine, theophylline, and substances with antimuscarinic potential. Second, drugs with local toxicity may produce de novo damage including inflammation, strictures, ulcers, and bleeding. Notorious examples are alendronate, certain antibiotics including tetracyclines and clindamycin, all NSAIDs/aspirin, quinidine, potassium chloride, and ferrous sulfate. Cyclooxygenase-2 inhibitors may be devoid of such toxicity, but may damage the mucosa by interfering with regenerative cell proliferation. The galenic formulation can modulate the risk of oesophageal injury. For this reason, medicines containing the same potentially toxic ingredient may be less exchangeable than commonly thought. Diagnostic gold standard is endoscopy. The best treatment is removal of the offending drug and supportive care. Prevention requires a re-appraisal of the drug's indication and adherence to guidelines of optimal drug intake including ingestion in an upright position and swallowing with enough fluid. The clinical relevance of drug-induced oesophageal injury and the feasibility of therapeutic alternatives are individually addressed. PMID:12946250

  12. Preference pulses induced by reinforcement.

    PubMed

    Hachiga, Yosuke; Sakagami, Takayuki; Silberberg, Alan

    2014-11-01

    Eight rats responded on concurrent Variable-Ratio 20 Extinction schedules for food reinforcement. The assignment of variable-ratio reinforcement to a left or right lever varied randomly following each reinforcer, and was cued by illumination of a stimulus light above that lever. Postreinforcement preference levels decreased substantially and reliably over time when the lever that just delivered reinforcement was now in extinction; however, if that lever was once again associated with variable ratio, this decrease in same-lever preference tended to be small, and for some subjects, not in evidence. The changes in preference level to the extinction lever were well described by a modified version of Killeen, Hanson, and Osborne's (1978) induction model. Consistent with this model's attribution of preference change to induction, we attribute preference change in this report to a brief period of reinforcer-induced arousal that energizes responding to the lever that delivered the last reinforcer. After a few seconds, this induced responding diminishes, and the operant responding that remains comes under the control of the stimulus light cuing the lever providing variable-ratio reinforcement. PMID:25270509

  13. Hydroxycut-induced Liver Toxicity

    PubMed Central

    Kaswala, DH; Shah, S; Patel, N; Raisoni, S; Swaminathan, S

    2014-01-01

    In the recent era, use of various nutritional supplements is highly encouraged amongst the people of United States. Weight loss supplements are major part of the nutritional supplements and their usage is unregulated in the US. Obesity is a major health concern in the US and Americans spend around $30 billion a year for weight loss supplements. At times, these supplements can be responsible for documented or undocumented adverse drug effects. The health consequences related to these supplements are often overlooked by the general public, even though FDA issues advisories regarding them. One common supplement used for weight loss was Hydroxycut (Iovate Health Sciences Research, Oakville, Ontario, Canada). Hydroxycut was recalled from the market after a FDA warning in May 2009 because of 23 reports of serious health problems ranging from jaundice and elevated liver enzymes to liver damage. 1 This case report adds evidence for Hydroxycut - induced hepatotoxicity. A 27 year old man with right upper quadrant pain and jaundice was found to have elevated liver enzymes and was taking Hydroxycut along with other supplements. Liver biopsy showed drug induced hepatotoxicity. Discontinuation of Hydroxycut dramatically improved liver functions and related symptoms. PMID:24669349

  14. Optically induced parametric magnetic resonances

    NASA Astrophysics Data System (ADS)

    Jimenez, Ricardo; Knappe, Svenja; Kitching, John

    2011-05-01

    Optically pumped vector magnetometers based on zero-field resonances have reached very high sensitivities by operating at high atomic densities where dephasing due to spin-exchange collisions can be suppressed. Simplified setups, with just one laser beam have measured magnetic fields from the human brain and heart. A key feature in these magnetometers is the introduction of an rf magnetic field along the measurement axis to generate a parametric resonance. Lock-in detection of the transmitted light, at an odd harmonic of the modulation frequency, allows the reduction of the low frequency noise and generates a resonance with dispersive shape. Here we study a zero-field vector magnetometer where the parametric resonances are induced by the vector AC stark-shift of light. This approach does not produce any external magnetic field that could disturb the reading of other magnetometers in the vicinity and could provide an alternative in applications where an applied AC-field cannot be used. We have characterized the vector AC stark-shift effect of light on Rb atoms contained in a micromachined vapor cell with buffer gas. We have obtained parametric resonances induced by modulation of the light-shift. We also analyze the detunings and intensities of the light-shift beam that maintain the magnetometer within the spin-exchange relaxation-free regime.

  15. Plasmon-induced artificial photosynthesis.

    PubMed

    Ueno, Kosei; Oshikiri, Tomoya; Shi, Xu; Zhong, Yuqing; Misawa, Hiroaki

    2015-06-01

    We have successfully developed a plasmon-induced artificial photosynthesis system that uses a gold nanoparticle-loaded oxide semiconductor electrode to produce useful chemical energy as hydrogen and ammonia. The most important feature of this system is that both sides of a strontium titanate single-crystal substrate are used without an electrochemical apparatus. Plasmon-induced water splitting occurred even with a minimum chemical bias of 0.23 V owing to the plasmonic effects based on the efficient oxidation of water and the use of platinum as a co-catalyst for reduction. Photocurrent measurements were performed to determine the electron transfer between the gold nanoparticles and the oxide semiconductor. The efficiency of water oxidation was determined through spectroelectrochemical experiments aimed at elucidating the electron density in the gold nanoparticles. A set-up similar to the water-splitting system was used to synthesize ammonia via nitrogen fixation using ruthenium instead of platinum as a co-catalyst. PMID:26052419

  16. Ion-induced nuclear radiotherapy

    DOEpatents

    Horn, Kevin M. (Albuquerque, NM); Doyle, Barney L. (Albuquerque, NM)

    1996-01-01

    Ion-induced Nuclear Radiotherapy (INRT) is a technique for conducting radiosurgery and radiotherapy with a very high degree of control over the spatial extent of the irradiated volume and the delivered dose. Based upon the concept that low energy, ion induced atomic and nuclear reactions can be used to produce highly energetic reaction products at the site of a tumor, the INRT technique is implemented through the use of a conduit-needle or tube which conducts a low energy ion beam to a position above or within the intended treatment area. At the end of the conduit-needle or tube is a specially fabricated target which, only when struck by the ion beam, acts as a source of energetic radiation products. The inherent limitations in the energy, and therefore range, of the resulting reaction products limits the spatial extent of irradiation to a pre-defined volume about the point of reaction. Furthermore, since no damage is done to tissue outside this irradiated volume, the delivered dose may be made arbitrarily large. INRT may be used both as a point-source of radiation at the site of a small tumor, or as a topical bath of radiation to broad areas of diseased tissue.

  17. Numerical calculation for cavitation flow of inducer

    NASA Astrophysics Data System (ADS)

    Ning, C.; Wang, Y.; Zhu, Z. T.; Xie, S. F.; Zhao, L. F.; Liu, Z. C.

    2015-01-01

    Inducer has significant effect on improving the cavitation characteristic of centrifugal pump. Several inducers were designed and modeled by Pro/E software. The mesh of flow field was done by ICEM and then was imported to ANSYS CFX to analyze the inducer's cavitation characteristic. Effects of the blade number on the performance of an inducer are investigated in the present paper. The inducers were designed on the basis of identical design flow rate and identical pressure elevation at nominal flow rate. The study focuses on the steady behavior of the inducers in cavitating conditions. Evolutions of performance, torque, mass flow rate, and amplitude of radial forces on the shaft according to the inlet pressure are considered. Furthermore, cavitation instabilities are analyzed in the study. The purpose of the present study is to investigate the pressure distribution and vapour volume fraction distribution through numerical simulations using the Navier-stokes solver with computational fluid dynamics (CFD) code.

  18. The mechanism of PDT-induced apoptosis

    NASA Astrophysics Data System (ADS)

    Cai, Xiongwei; Liu, Timon C.; Ding, Xin-Min; Gu, Ying; Liu, Fan-Guang; Liu, Song-Hao

    2003-12-01

    Photodynamic therapy (PDT) can induce apoptosis in many cancer cells in vitro and in tumors in vivo. Cells become more oxidation with PDT, and maintain differentiation and proliferation, go apoptosis and necrosis with the increase of reactive oxygen species (ROS) concentration. ROS can induce apoptosis through mitochondria by inhibiting respiration chain or oxidative phosphorylation or damaging mitochondrial membrane. ROS can initiate apoptosis through endoplamic reticulum(ER) by opening Ca2+ channel or starting unfold protein response (UPR). ROS can also induce apoptosis through Golgi by producing ganglioside GD3 by use of ceramide, which induces apoptosis by activating caspase-3, JNK and p38 MAPK. It can also induce apoptosis by activating Bip (mitochondria-dependant) or preocaspase-12 (mitochondria- independent) or inhibiting protein synthesizing. There are so complicated cross-talking among different signal pathways or organnells that we think PDT-induced apoptosis is mediated by multiplex pathways and excessive levels in a refined network.

  19. Fondaparinux in heparin-induced thrombocytopenia.

    PubMed

    Gevaert, Andreas; Smets, Hilde; Vercauteren, Roeland

    2013-10-01

    Heparin-induced thrombocytopenia is a potentiallylife-threatening complication of heparin or low-molecular-weight heparin administration. We describe the case of a patient with heparin-induced thrombocytopenia complicated by pulmonary embolism, successfully treated with fondaparinux, a factor Xa inhibitor. We also review the literature regarding the use of this anticoagulant in heparin-induced thrombocytopenia complicated by thrombosis. Few treatment options are available in Belgium, and there is little evidence regarding newer anticoagulants. PMID:24283115

  20. Cyclooxygenase-1 and -2: Molecular Targets for Cervical Neoplasia

    PubMed Central

    Kim, Hee Seung; Kim, Taehun; Kim, Mi-Kyung; Suh, Dong Hoon; Chung, Hyun Hoon; Song, Yong Sang

    2013-01-01

    Cyclooxygenase (COX) is a key enzyme responsible for inflammation, converting arachidonic acid to prostaglandin and thromboxane. COX has at least two isoforms, COX-1 and COX-2. While COX-1 is constitutively expressed in most tissues for maintaining physiologic homeostasis, COX-2 is induced by inflammatory stimuli including cytokines and growth factors. Many studies have shown that COX-2 contributes to cancer development and progression in various types of malignancy including cervical cancer. Human papillomavirus, a necessary cause of cervical cancer, induces COX-2 expression via E5, E6 and E7 oncoproteins, which leads to prostaglandin E2 increase and the loss of E-cadherin, promotes cell proliferation and production of vascular endothelial growth factor. It is strongly suggested that COX-2 is associated with cancer development and progression such as lymph node metastasis. Many studies have suggested that non-selective COX-2 inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors might show anti-cancer activity in COX-2 -dependent and -independent manners. Two phase II trials for patients with locally advanced cervical cancer showed that celecoxib increased toxicities associated with radiotherapy. Contrary to these discouraging results, two phase II clinical trials, using rofecoxib and celecoxib, demonstrated the promising chemopreventive effect for patients with cervical intraepithelial neoplasia 2 or 3. However, these agents cause a rare, but serious, cardiovascular complication in spite of gastrointestinal protection in comparison with NSAIDs. Recent pharmacogenomic studies have showed that the new strategy for overcoming the limitation in clinical application of COX-2 inhibitors shed light on the use of them as a chemopreventive method. PMID:25337538