101 results on '"D'Agostino, Donna M."'
Search Results
2. Functional properties and sequence variation of HTLV-1 p13
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Omsland, Maria, Silic-Benussi, Micol, Moles, Ramona, Sarkis, Sarkis, Purcell, Damian F. J., Yurick, David, Khoury, Georges, D’Agostino, Donna M., Ciminale, Vincenzo, and Franchini, Genoveffa
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- 2020
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3. Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis
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Silic-Benussi, Micol, Scattolin, Gloria, Cavallari, Ilaria, Minuzzo, Sonia, del Bianco, Paola, Francescato, Samuela, Basso, Giuseppe, Indraccolo, Stefano, D’Agostino, Donna M., and Ciminale, Vincenzo
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- 2018
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4. Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus.
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Silic-Benussi, Micol, Sharova, Evgeniya, Corradin, Alberto, Urso, Loredana, Raimondi, Vittoria, Cavallari, Ilaria, Buldini, Barbara, Francescato, Samuela, Minuzzo, Sonia A., D'Agostino, Donna M., and Ciminale, Vincenzo
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ARRHYTHMIA ,VERAPAMIL ,MTOR inhibitors ,PENTOSE phosphate pathway ,EVEROLIMUS ,GLUCOSE-6-phosphate dehydrogenase - Abstract
New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150
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Ghisi, Margherita, Corradin, Alberto, Basso, Katia, Frasson, Chiara, Serafin, Valentina, Mukherjee, Subhamoy, Mussolin, Lara, Ruggero, Katia, Bonanno, Laura, Guffanti, Alessandro, De Bellis, Gianluca, Gerosa, Gino, Stellin, Giovanni, D'Agostino, Donna M., Basso, Giuseppe, Bronte, Vincenzo, Indraccolo, Stefano, Amadori, Alberto, and Zanovello, Paola
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- 2011
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6. Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells
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Silic-Benussi, Micol, Cavallari, Ilaria, Vajente, Nicola, Vidali, Silvia, Chieco-Bianchi, Luigi, Di Lisa, Fabio, Saggioro, Daniela, D'Agostino, Donna M., and Ciminale, Vincenzo
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- 2010
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7. Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K + permeability: A new member of the viroporin family?
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Silic-Benussi, Micol, Marin, Oriano, Biasiotto, Roberta, D’Agostino, Donna M., and Ciminale, Vincenzo
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- 2010
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8. MiR-150 in HTLV-1 infection and T-cell transformation.
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D'Agostino, Donna M., Raimondi, Vittoria, Silic-Benussi, Micol, and Ciminale, Vincenzo
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ADULT T-cell leukemia ,T cells ,HEMATOLOGIC malignancies ,LIFE cycles (Biology) ,VIRAL proteins - Abstract
Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus that persistently infects CD4+ T-cells, and is the causative agent of adult T-cell leukemia/lymphoma (ATLL), tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and several inflammatory diseases. T-cell transformation by HTLV-1 is driven by multiple interactions between viral regulatory proteins and host cell pathways that govern cell proliferation and survival. Studies performed over the last decade have revealed alterations in the expression of many microRNAs in HTLV-1-infected cells and ATLL cells, and have identified several microRNA targets with roles in the viral life cycle and host cell turnover. This review centers on miR-150-5p, a microRNA whose expression is temporally regulated during lymphocyte development and altered in several hematological malignancies. The levels of miR-150-5p are reduced in many HTLV-1-transformed- and ATLL-derived cell lines. Experiments in these cell lines showed that downregulation of miR-150-5p results in activation of the transcription factor STAT1, which is a direct target of the miRNA. However, data on miR-150-5p levels in freshly isolated ATLL samples are suggestive of its upregulation compared to controls. These apparently puzzling findings highlight the need for more in-depth studies of the role of miR-150-5p in HTLV-1 infection and pathogenesis based on knowledge of miR-150-5p-target mRNA interactions and mechanisms regulating its function in normal leukocytes and hematologic neoplasms. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Identification of novel monocistronic HTLV-1 mRNAs encoding functional Rex isoforms
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Rende, Francesca, Cavallari, Ilaria, Andresen, Vibeke, Valeri, Valerio W, D'Agostino, Donna M, Franchini, Genoveffa, and Ciminale, Vincenzo
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- 2015
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10. Kinetics and intracellular compartmentalization of HTLV-1 gene expression
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D'Agostino Donna M, Taylor Graham P, Jacobson Steven, Tanaka Yuetsu, Toffolo Gianna M, Toulza Frederic, Silic-Benussi Micol, Corradin Alberto, Cavallari Ilaria, Rende Francesca, Bangham Charles R M, and Ciminale Vincenzo
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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11. MicroRNA expression in HTLV-1 infection and pathogenesis
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Zanovello Paola, Corti Giorgio, De Bellis Gianluca, Guffanti Alessandro, Basso Katia, Corradin Alberto, Pise-Masison Cynthia A, Bortoluzzi Stefania, Biasiolo Marta, Ruggero Katia, D'Agostino Donna M, Bronte Vincenzo, and Ciminale Vincenzo
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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12. Suppression of tumor growth and cell proliferation by [p13.sup.11], a mitochondrial protein of human T cell leukemia virus type 1
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Silic-Benussi, Micol, Cavallari, Ilaria, Zorzan, Tatiana, Rossi, Elisabetta, Hiraragi, Hajime, Rosato, Antonio, Horie, Kyoji, Saggioro, Daniela, Lairmore, Michael D., Willems, Luc, Chieco-Bianchi, Luigi, D'Agostino, Donna M., and Ciminale, Vincenzo
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Leukemia -- Research ,T cells -- Research ,Science and technology - Abstract
Human T cell leukemia virus type I encodes an 'accessory' protein named [p13.sup.11] that is targeted to mitochondria and triggers a rapid flux of [K.sup.+] and [Ca.sup.2+] across the inner membrane. In this study, we investigated the effects of [p13.sup.11] on tumorigenicity in vivo and on cell growth in vitro. Results showed that [p13.sup.11] significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing [p13.sup.11] exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the [p13.sup.11] cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The [p13.sup.11] cell lines exhibited an enhanced response to [Ca.sup.2+]-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine, [p13.sup.11]-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of [p13.sup.11] as a negative regulator of cell growth and underscore a link between mitochondria, [Ca.sup.2+] signaling, and tumorigenicity.
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- 2004
13. The MicroRNA Regulatory Network in Normal- and HTLV-1-Transformed T Cells
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DʼAgostino, Donna M., Zanovello, Paola, Watanabe, Toshiki, and Ciminale, Vincenzo
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- 2012
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14. Mitochondrial targeting of the p13II protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I)
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Ciminale, Vincenzo, Zotti, Lorenza, D'Agostino, Donna M, Ferro, Tiziana, Casareto, Luca, Franchini, Genoveffa, Bernardi, Paolo, and Chieco-Bianchi, Luigi
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- 1999
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15. Mitochondria as Functional Targets of Proteins Coded by Human Tumor Viruses
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DʼAgostino, Donna M., Bernardi, Paolo, Chieco-Bianchi, Luigi, and Ciminale, Vincenzo
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- 2005
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16. In Situ Analysis of Human Menin in Normal and Neoplastic Pancreatic Tissues: Evidence for Differential Expression in Exocrine and Endocrine Cells
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Cavallari, Ilaria, D’Agostino, Donna M., Ferro, Tiziana, Rosato, Antonio, Barzon, Luisa, Pasquali, Claudio, Fogar, Paola, Theodoropoulou, Marily, Esposito, Giovanni, Boscaro, Marco, Pagotto, Uberto, Tebaldi, Elisabetta, Fallo, Francesco, Chieco-Bianchi, Luigi, and Ciminale, Vincenzo
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- 2003
17. Expression and functional properties of proteins encoded in the x-II ORF of HTLV-I
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D'Agostino, Donna M., Zotti, Lorenza, Ferro, Tiziana, Cavallori, Ilaria, Silic-Benussi, Micol, Chieco-Bianchi, Luigi, and Ciminale, Vincenzo
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- 2001
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18. Unique features of HIV-1 Rev protein phosphorylation by protein kinase CK2 (‘casein kinase-2’)
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Marin, Oriano, Sarno, Stefania, Boschetti, Marco, Pagano, Mario A, Meggio, Flavio, Ciminale, Vincenzo, D’Agostino, Donna M, and Pinna, Lorenzo A
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- 2000
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19. Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue.
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D'Agostino, Donna M., Cavallari, Ilaria, Romanelli, Maria Grazia, and Ciminale, Vincenzo
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GENETIC regulation ,HTLV-I ,POLIO ,RNA splicing - Abstract
Human T-lymphotropic virus type 1 (HTLV-1) and other members of the Deltaretrovirus genus code for a regulatory protein named Rex that binds to the Rex-responsive element present on viral mRNAs. Rex rescues viral mRNAs from complete splicing or degradation and guides them to the cytoplasm for translation. The activity of Rex is essential for expression of viral transcripts coding for the virion components and thus represents a potential target for virus eradication. We present an overview of the functional properties of the HTLV-1 and HTLV-2 Rex proteins (Rex-1 and Rex-2), outline mechanisms controlling Rex function, and discuss similarities and differences in the sequences of Rex coded by HTLV-1, -2, -3, and -4 that may influence their molecular anatomy and functional properties. [ABSTRACT FROM AUTHOR]
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- 2019
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20. Mitochondrial Proteins Coded by Human Tumor Viruses.
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Cavallari, Ilaria, Scattolin, Gloria, Silic-Benussi, Micol, Raimondi, Vittoria, D'Agostino, Donna M., and Ciminale, Vincenzo
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MITOCHONDRIAL proteins ,ONCOGENIC viruses ,CELLULAR bioenergetics - Abstract
Viruses must exploit the cellular biosynthetic machinery and evade cellular defense systems to complete their life cycles. Due to their crucial roles in cellular bioenergetics, apoptosis, innate immunity and redox balance, mitochondria are important functional targets of many viruses, including tumor viruses. The present review describes the interactions between mitochondria and proteins coded by the human tumor viruses human T-cell leukemia virus type 1, Epstein-Barr virus, Kaposi’s sarcoma-associated herpesvirus, human hepatitis viruses B and C, and human papillomavirus, and highlights how these interactions contribute to viral replication, persistence and transformation. [ABSTRACT FROM AUTHOR]
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- 2018
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21. Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs
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Rende, Francesca, Cavallari, Ilaria, Corradin, Alberto, Silic-Benussi, Micol, Toulza, Frederic, Toffolo, Gianna M., Tanaka, Yuetsu, Jacobson, Steven, Taylor, Graham P., D'Agostino, Donna M., Bangham, Charles R.M., and Ciminale, Vincenzo
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- 2011
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22. A circulating miRNA assay as a first-line test for prostate cancer screening.
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Sharova, Evgeniya, Grassi, Angela, Marcer, Anna, Ruggero, Katia, Pinto, Francesco, Bassi, Pierfrancesco, Zanovello, Paola, Zattoni, Filiberto, D'Agostino, Donna M, Iafrate, Massimo, and Ciminale, Vincenzo
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PROSTATE tumors ,RNA ,BENIGN prostatic hyperplasia ,EARLY detection of cancer ,DIAGNOSIS - Abstract
Background: Prostate cancer (PCa) screening currently relies on prostate-specific antigen (PSA) testing and digital rectal examination. However, recent large-scale studies have questioned the long-term efficacy of these tests, and biomarkers that accurately identify PCa are needed.Methods: We analysed the levels of circulating microRNAs (miRNAs) in patients with elevated PSA who were diagnosed with either localised PCa (n=36) or benign prostatic hyperplasia (BPH, n=31) upon biopsy. Real-time RT-PCR with Taqman probes was used to measure plasma levels of miRNAs. To circumvent problems associated with circulating miRNA quantitation, we computed the expression ratios of upregulated and downregulated miRNAs.Results: The miR-106a/miR-130b and miR-106a/miR-223 ratios were significantly different between the biopsy-positive and BPH groups (P<0.0001), and yielded statistical power values that were >0.99. Both miRNA ratios were highly sensitive and more specific than PSA in discriminating localised PCa from BPH. Receiver operating characteristic curve analysis revealed area under curve values of 0.81 (miR-106a/miR-130b) and 0.77 (miR-106a/miR-223).Conclusions: Testing for circulating miR-106a/miR-130b and miR-106a/miR-223 ratios may reduce the costs and morbidity of unnecessary biopsies and is feasible for large-scale screening, as it requires measuring only three miRNAs. [ABSTRACT FROM AUTHOR]- Published
- 2016
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23. Converging Strategies in Expression of Human Complex Retroviruses.
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Cavallari, Ilaria, Rende, Francesca, D'Agostino, Donna M., and Ciminale, Vincenzo
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RETROVIRUSES ,VIRUS diseases ,GENE expression ,MESSENGER RNA ,GENES - Abstract
The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as 'simple' and 'complex', respectively. Expression of most of these extra genes is achieved through the generation of alternatively spliced mRNAs. The present review summarizes the genetic organization and expression strategies of human complex retroviruses and highlights the converging mechanisms controlling their life cycles. [ABSTRACT FROM AUTHOR]
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- 2011
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24. Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?
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Silic-Benussi, Micol, Marin, Oriano, Biasiotto, Roberta, D’Agostino, Donna M., and Ciminale, Vincenzo
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HTLV ,PERMEABILITY ,OXYGEN in the body ,APOPTOSIS ,MEMBRANE proteins ,MITOCHONDRIA ,POTASSIUM channels ,HOMEOSTASIS - Abstract
Abstract: Human T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K
+ current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K+ and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K+ channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability. [Copyright &y& Elsevier]- Published
- 2010
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25. Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal adenocarcinoma.
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Cavallari, Ilaria, Silic-Benussi, Micol, Rende, Francesca, Martines, Annalisa, Fogar, Paola, Basso, Daniela, Vella, Manuela Della, Pedrazzoli, Sergio, Herman, James G., Chieco-Bianchi, Luigi, Esposito, Giovanni, Ciminale, Vincenzo, and D'Agostino, Donna M.
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- 2009
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26. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers.
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Cavallari, Ilaria, Ciccarese, Francesco, Sharova, Evgeniya, Urso, Loredana, Raimondi, Vittoria, Silic-Benussi, Micol, D'Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
EPITHELIAL cell tumors ,MICRORNA ,EPITHELIAL-mesenchymal transition ,CELLULAR signal transduction ,TUMOR suppressor genes ,TUMOR markers ,EPITHELIAL cells ,BODY fluid examination ,PHENOTYPES - Abstract
Simple Summary: MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression by blocking translation or inducing degradation of specific gene transcripts. The miR-200 family controls the expression of many genes that play important roles in cancer cells. One of the main pathways controlled by these miRNAs, termed epithelial-mesenchymal transition (EMT), is an essential component of the invasive growth program of solid tumors. The miR-200 family has thus been the focus of many studies aimed at discovering strategies to block cancer cell growth and disease progression. In addition, the miR-200 family miRNAs have been investigated as possible circulating cancer biomarkers. Here we provide an overview of factors that influence miR-200 family expression and target genes relevant to tumor development, followed by a summary of their potential utility as noninvasive biomarkers for selected cancers. The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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27. Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human I cell leukemia virus, type 1.
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Sillc-Benussi, Micol, Cavallari, Ilaria, Zorzan, Tatiana, Rossi, Elisabetta, Hiraragi, Hajime, Rosato, Antonio, Hone, Kyoji, Saggioro, Daniela, Lairmore, Michael D., Wiliems, Luc, Chieco-Bianchi, Luigi, D'Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
T cells ,HTLV-I ,CELL proliferation ,LEUKEMIA ,ONCOLOGY ,GENETICS ,PROTEINS - Abstract
Human T cell leukemia virus type 1 encodes an "accessory" protein named p13
II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell tines exhibited an enhanced response to Ca2+ -mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine, p13II -expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
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28. Comprehensive Profiling of Hypoxia-Related miRNAs Identifies miR-23a-3p Overexpression as a Marker of Platinum Resistance and Poor Prognosis in High-Grade Serous Ovarian Cancer.
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Todeschini, Paola, Salviato, Elisa, Romani, Chiara, Raimondi, Vittoria, Ciccarese, Francesco, Ferrari, Federico, Tognon, Germana, Marchini, Sergio, D'Incalci, Maurizio, Zanotti, Laura, Ravaggi, Antonella, Odicino, Franco, Sartori, Enrico, D'Agostino, Donna M., Samaja, Michele, Romualdi, Chiara, and Bignotti, Eliana
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PROTEIN metabolism ,PLATINUM compounds ,EVALUATION of medical care ,SURVIVAL ,REVERSE transcriptase polymerase chain reaction ,OVARIAN tumors ,MICRORNA ,INDIVIDUALIZED medicine ,APOPTOSIS ,GENE expression ,TUMOR markers ,TUMORS ,POLYMERASE chain reaction ,HYPOXEMIA ,DRUG resistance in cancer cells - Abstract
Simple Summary: In the present paper, we identified miR-23a-3p, a hypoxia regulated-microRNA (miRNA), as a potential biomarker of chemoresistance and poor outcome in two independent cohorts of high-grade serous ovarian carcinoma (HGSOC) patients. Then, we predicted the involvement of miR-23a-3p in the platinum resistance pathway, together with its target APAF-1 gene, and validated their anticorrelation and association with platinum response in HGSOC patients and cell lines. We propose that the evaluation of miR-23a-3p expression may provide important clinical indications on patients not responding to platinum treatment and that the miR23a-3p/APAF1 axis could be considered a possible target for personalized medicine in HGSOC patients. The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. Mitochondrial targeting of the p13II protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I).
- Author
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Ciminale, Vincenzo, Zotti, Lorenza, D'Agostino, Donna M, Ferro, Tiziana, Casareto, Luca, Franchini, Genoveffa, Bernardi, Paolo, and Chieco-Bianchi, Luigi
- Subjects
HTLV ,GENOMES ,IMMUNOFLUORESCENCE ,PROTEINS ,MITOCHONDRIA - Abstract
The X region of the HTLV-I genome contains four major open reading frames (ORFs), two of which, termed x-I and x-II, are of still undefined biological significance. By indirect immunofluorescence and dual labeling with marker proteins, we demonstrate that p13
II , an 87-amino acid protein coded by the x-II ORF, is selectively targeted to mitochondria. Mutational analysis revealed that mitochondrial targeting of p13II is directed by an atypical 10-amino acid signal sequence that is not cleaved upon import and is able to target the Green Fluorescent Protein to mitochondria. Expression of p13II results in specific alterations of mitochondrial morphology and distribution from a typical string-like, dispersed network to round-shaped clusters, suggesting that p13II might interfere with processes relying on an intact mitochondrial architecture. Functional studies of mitochondria with the cationic fluorochrome tetramethylrhodamine revealed that a subpopulation of the cells with p13II -positive mitochondria show a disruption in the mitochondrial inner membrane potential (Δψ), an early event observed in cells committed to apoptosis. Taken together, these results suggest novel virus-cell interactions that might be important in HTLV-I replication and/or pathogenicity. [ABSTRACT FROM AUTHOR]- Published
- 1999
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30. Coding potential of the X region of human T-cell leukemia/lymphotropic virus type II.
- Author
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Ciminale, Vincenzo and D'Agostino, Donna M.
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HTLV , *GENE expression - Abstract
Discusses the expression strategies leading to the increased coding potential of the X region of the complex human retrovirus HTLV-II. Possible basis for pathogenic differences between HTLV-II and HTLV-I; Alternative splicing and translation of more than one protein of the same mRNA; Complex life cycle and pathogenicity of HTLV-I and HTLV-II.
- Published
- 1996
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31. Prognostic Stratification of Bladder Cancer Patients with a MicroRNA-Based Approach.
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Cavallari, Ilaria, Grassi, Angela, Del Bianco, Paola, Aceti, Alberto, Zaborra, Carlotta, Sharova, Evgeniya, Bertazzolo, Irene, D'Agostino, Donna M., Iafrate, Massimo, and Ciminale, Vincenzo
- Subjects
BLADDER tumors ,BODY fluid examination ,CANCER patients ,CANCER relapse ,DECISION trees ,GENETIC techniques ,REGRESSION analysis ,RISK assessment ,SURVIVAL analysis (Biometry) ,TUMOR markers ,PREDICTIVE tests ,PROPORTIONAL hazards models ,MICRORNA ,DISEASE complications ,DISEASE risk factors - Abstract
Simple Summary: The majority of patients with bladder cancer are diagnosed before the malignant cells invade the bladder's muscle wall, and can be treated with surgery. These patients are nevertheless at high risk of disease recurrence and progression to muscle-invasive disease, and must undergo periodic cystoscopy and urine cytology, procedures that are burdensome for the patient and for the healthcare system. We set out to identify a follow-up/risk assessment test that analyzes the levels of a specific class of RNA molecules (microRNAs) in urine samples. Results led to the discovery of a panel of microRNAs in urine samples that identifies high-risk bladder cancer patients with high accuracy and predicts event-free survival. This urine microRNA assay thus holds promise as a noninvasive alternative to current methods for bladder cancer follow-up. Robust non-invasive tests for prognostic stratification of bladder cancer (BCa) patients are in high demand. Following a comprehensive analysis of studies on BCa, we selected a panel of 29 microRNAs (miRNAs) and analyzed their levels in urine and plasma samples in a prospective cohort of 63 BCa patients (32 at high risk of recurrence and 31 low-risk cases) and 37 healthy controls using RT-qPCR. To design an assay suitable for large-scale testing, we applied a hierarchical pipeline to select the miRNAs that were not affected by confounding factors such as haematuria and urine specific gravity, and exceeded stringent cut-off criteria (fold change > 2.5 and p-value < 0.005). Using a two-step decision tree based on the urine levels of miR-34a-5p, miR-200a-3p and miR-193a-5p, normalized against miR-125b-5p, patients could be classified as high- or low-risk with a sensitivity of 0.844, specificity of 0.806 and accuracy of 0.825. Furthermore, univariate Cox proportional hazards regression analyses indicated that increased urine levels of miR-29a-3p, miR-34a-5p, miR-193a-5p, miR-200c-3p, miR-205-5p and miR-532-5p were associated with a shorter event-free survival (hazard ratios > 3.1, p-value < 0.05). Taken together, our findings suggest that measuring the urine levels of these miRNAs could provide a novel cost-effective, noninvasive test for risk assessment of BCa patients. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
32. NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ.
- Author
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Fochi, Stefania, Ciminale, Vincenzo, Trabetti, Elisabetta, Bertazzoni, Umberto, D'Agostino, Donna M., Zipeto, Donato, and Romanelli, Maria Grazia
- Subjects
HTLV-I ,ADULT T-cell leukemia ,MICRORNA ,VIRAL proteins ,LEUCINE zippers - Abstract
The risk of developing adult T-cell leukemia/lymphoma (ATLL) in individuals infected with human T-cell lymphotropic virus 1 (HTLV-1) is about 3–5%. The mechanisms by which the virus triggers this aggressive cancer are still an area of intensive investigation. The viral protein Tax-1, together with additional regulatory proteins, in particular HTLV-1 basic leucine zipper factor (HBZ), are recognized as relevant viral factors required for both viral replication and transformation of infected cells. Tax-1 deregulates several cellular pathways affecting the cell cycle, survival, and proliferation. The effects of Tax-1 on the NF-κB pathway have been thoroughly studied. Recent studies also revealed the impact of Tax-1 and HBZ on microRNA expression. In this review, we summarize the recent progress in understanding the contribution of HTLV-1 Tax- and HBZ-mediated deregulation of NF-κB and the microRNA regulatory network to HTLV-1 pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. MicroRNA expression in HTLV-1 infection and pathogenesis.
- Author
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D'Agostino, Donna M., Ruggero, Katia, Biasiolo, Marta, Bortoluzzi, Stefania, Pise-Masison, Cynthia A., Corradin, Alberto, Basso, Katia, Guffanti, Alessandro, De Bellis, Gianluca, Corti, Giorgio, Zanovello, Paola, Bronte, Vincenzo, and Ciminale, Vincenzo
- Subjects
- *
HTLV-I , *MESSENGER RNA , *GENE expression - Abstract
An abstract of the research paper titled,"MicroRNA expression in the Human T-cell leukemia virus type 1 (HTLV-1) infection and pathogenesis ," is presented.
- Published
- 2011
- Full Text
- View/download PDF
34. Kinetics and intracellular compartmentalization of HTLV-1 gene expression.
- Author
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Rende, Francesca, Cavallari, Ilaria, Corradin, Alberto, Silic-Benussi, Micol, Toulza, Frederic, Toffolo, Gianna M., Tanaka, Yuetsu, Jacobson, Steven, Taylor, Graham P., D'Agostino, Donna M., Bangham, Charles R. M., and Ciminale, Vincenzo
- Subjects
HTLV-I ,GENE expression - Abstract
An abstract of the research paper titled," Kinetics and intracellular compartmentalization of the Human T-cell leukemia virus type 1 (HTLV-1) gene expression," is presented.
- Published
- 2011
- Full Text
- View/download PDF
35. Control of ROS production and T-cell turnover by HTLV-p13.
- Author
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Silic-Benussi, Micol, Cavallari, Ilaria, Chieco-Bianchi, Luigi, di Lisa, Fabio, D'Agostino, Donna M., Bernardi, Paolo, and Ciminale, Vincenzo
- Subjects
HTLV ,REACTIVE oxygen species ,T cells - Abstract
An abstract of the research paper titled,"Control of reactive oxygen species (ROS) production and T-cell turnover by the Human T-cell leukemia virus type 13 (HTLV-p13)," is presented.
- Published
- 2011
- Full Text
- View/download PDF
36. Mitochondria as Functional Targets of Proteins Coded by Human Tumor Viruses.
- Author
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D'Agostino, Donna M., Bernardi, Paolo, Chieco-Bianchi, Luigi, and Vincenzo, Vincenzo
- Subjects
MITOCHONDRIA - Abstract
An abstract of "Mitochondria as Functional Targets of Proteins Coded by Human Tumor Viruses," by Donna M. D'Agostin, Paolo Bernardi, and Vincenzo is presented.
- Published
- 2005
- Full Text
- View/download PDF
37. Expression and Characterization of Proteins Produced by mRNAs Spliced into the X Region of the Human T-Cell Leukemia/Lymphotropic Virus Type II
- Author
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Ciminale, Vincenzo, D'Agostino, Donna M., Zotti, Lorenza, Franchini, Genoveffa, Felber, Barbara K., and Chieco-Bianchi, Luigi
- Published
- 1995
- Full Text
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38. Functional Domain Structure of Human T-Cell Leukemia Virus Type 2 Rex.
- Author
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Narayan, Murli, Younis, Ihab, D'Agostino, Donna M., and Green, Patrick L.
- Subjects
- *
HTLV , *VIRAL proteins , *VIRAL genetics - Abstract
The Rex protein of human T-cell leukemia virus (HTLV) acts posttranscriptionally to induce the cytoplasmic expression of the unspliced and incompletely spliced viral RNAs encoding the viral structural and enzymatic proteins and is therefore essential for efficient viral replication. Rex function requires nuclear import, RNA binding, multimerization, and nuclear export. In addition, it has been demonstrated that the phosphorylation status of HTLV-2 Rex (Rex-2) correlates with RNA binding and inhibition of splicing in vitro. Recent mutational analyses of Rex-2 revealed that the phosphorylation of serine residues 151 and 153 within a novel carboxy-terminal domain is critical for function in vivo. To further define the functional domain structure of Rex-2, we evaluated a panel of Rex-2 mutants for subcellular localization, RNA binding capacity, multimerization and trans-dominant properties, and the ability to shuttle between the nucleus and the cytoplasm. Rex-2 mutant S151A,S153A, which is defective in phosphorylation and function, showed diffuse cytoplasmic staining, whereas mutant S151D,S153D, previously shown to be functional and in a conformation corresponding to constitutive phosphorylation, displayed increased intense speckled staining in the nucleoli. In vivo RNA binding analyses indicated that mutant S151A, SI53A failed to efficiently bind target RNA, while its phosphomimetic counterpart, S151D,S153D, bound twofold more RNA than wild-type Rex-2. Taken together, these findings provide direct evidence that the phosphorylation status of Rex-2 is linked to cellular trafficking and RNA binding capacity. Mutants with substitutions in either of the two putative multimerization domains or in the putative activation domain-nuclear export signal displayed a dominant negative phenotype as well as defects in multimerization and nucleocytoplasmic shuttling. Several carboxy-terminal mutants that displayed wild-type levels of phosphorylation and localized to the nucleolus were also partially impaired in shuttling. This is consistent with the hypothesis that the carboxy terminus of Rex-2 contains a novel domain that is required for efficient shuttling. This work thus provides a more detailed functional domain map of Rex-2 and further insight into its regulation of HTLV replication. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
39. Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence.
- Author
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Cavallari, Ilaria, Rende, Francesca, Bona, Marion K., Sztuba-Solinska, Joanna, Silic-Benussi, Micol, Tognon, Martina, LeGrice, Stuart F. J., Franchini, Genoveffa, D'Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
- *
GENE expression , *HTLV-I , *MITOSIS , *NUCLEOTIDE sequence , *CELL cycle , *INFECTIOUS disease transmission - Abstract
Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2=-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. Small Noncoding RNAs in Cells Transformed by Human T-Cell Leukemia Virus Type 1: a Role for a tRNA Fragment as a Primer for Reverse Transcriptase.
- Author
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Ruggero, Katia, Guffanti, Alessandro, Corradin, Alberto, Sharma, Varun Kumar, De Bellis, Gianluca, Corti, Giorgio, Grassi, Angela, Zanovello, Paola, Bronte, Vincenzo, Ciminale, Vincenzo, and D'Agostino, Donna M.
- Subjects
- *
T-cell lymphoma , *HTLV-I , *TRANSFER RNA , *DNA primers , *REVERSE transcriptase - Abstract
The present study employed mass sequencing of small RNA libraries to identify the repertoire of small noncoding RNAs expressed in normal CD4+ T cells compared to cells transformed with human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma (ATLL). The results revealed distinct patterns of microRNA expression in HTLV-1- infected CD4+ T-cell lines with respect to their normal counterparts. In addition, a search for virus-encoded microRNAs yielded 2 sequences that originated from the plus strand of the HTLV-1 genome. Several sequences derived from tRNAs were expressed at substantial levels in both uninfected and infected cells. One of the most abundant tRNA fragments (tRF-3019) was derived from the 3= end of tRNA-proline. tRF-3019 exhibited perfect sequence complementarity to the primer binding site of HTLV-1. The results of an in vitro reverse transcriptase assay verified that tRF-3019 was capable of priming HTLV-1 reverse transcriptase. Both tRNA-proline and tRF-3019 were detected in virus particles isolated from HTLV-1-infected cells. These findings suggest that tRF-3019 may play an important role in priming HTLV-1 reverse transcription and could thus represent a novel target to control HTLV-1 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.
- Author
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Margherita Ghisi, Alberto Corradin, Katia Basso, Chiara Frasson, Valentina Serafin, Subhamoy Mukherjee, Mussolin, Lara, Ruggero, Katia, Bonanno, Laura, Guffanti, Alessandro, de Bellis, Gianluca, Gerosa, Gino, Stellin, Giovanni, D'Agostino, Donna M., Basso, Giuseppe, Bronte, Vincenzo, Indraccolo, Stefano, Amadori, Alberto, and Zanovello, Paola
- Subjects
- *
T-cell receptor genes , *ONTOGENY , *THYMUS , *CELL physiology , *CELL differentiation - Abstract
Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4+ and single-positive CD8+ maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4+ and CD8+ T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
42. Role of microRNAs in HTLV-1 infection and transformation
- Author
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Ruggero, Katia, Corradin, Alberto, Zanovello, Paola, Amadori, Alberto, Bronte, Vincenzo, Ciminale, Vincenzo, and D’Agostino, Donna M.
- Subjects
- *
HTLV-I , *GENETIC transformation , *GENE expression , *VIRAL proteins , *GENETIC transcription , *VIRAL genetics , *CELLULAR signal transduction - Abstract
Abstract: Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus that infects more than 20 million people worldwide, is the etiological agent of ATLL (adult T-cell leukemia/lymphoma), an aggressive leukemia of CD4+ T lymphocytes which arises in a small percentage of infected individuals after a long clinical latency. Tumor emergence is attributed primarily to the oncogenic activity of the viral protein Tax, which drives the expression of viral transcripts and controls the expression and function of a broad variety of host-cell genes involved in proliferation, genetic stability and apoptosis. Nevertheless, many aspects of HTLV-1 replication, persistence and pathogenesis remain to be understood. The emerging role of microRNAs in tumor development and viral infection has prompted investigations on the interactions between HTLV-1 and the microRNA regulatory network. In the present review we discuss recent data demonstrating changes in cellular microRNA expression in HTLV-1-infected cell lines and ATLL cells, and the functional impact of a subset microRNAs deregulated by HTLV-1 on cellular gene expression and signal transduction pathways. Mechanisms through which the viral proteins may influence microRNA expression are discussed. Results of searches for potential cellular microRNAs that target viral transcripts and for microRNAs produced by HTLV-1 are described. Observations along with regarding the expression of tRNA-derived small regulatory RNAs in HTLV-1-infected cells are presented. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
43. HTLV-1 p13, a small protein with a busy agenda
- Author
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Silic-Benussi, Micol, Biasiotto, Roberta, Andresen, Vibeke, Franchini, Genoveffa, D’Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
- *
HTLV-I , *APOPTOSIS , *POTASSIUM channels , *MITOCHONDRIA , *PARAPARESIS , *REACTIVE oxygen species , *CELL proliferation - Abstract
Abstract: Human T-cell leukemia virus type 1 (HTLV-1) infection is characterized by life-long persistence of the virus in the host. While most infected individuals remain asymptomatic, 3–5% will eventually develop adult T-cell leukemia/lymphoma (ATLL) or tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM) after a clinical latency that can span years (TSP/HAM) to decades (ATLL). The major oncogenic determinant among HTLV-1 proteins is the Tax transactivator, which influences the expression and function of a great number of cellular proteins, drives cell proliferation, reduces cell death, and induces genetic instability. The present review is focused on the current knowledge of p13, an HTLV-1 accessory protein targeted to the inner mitochondrial membrane and, under certain conditions, to the nucleus. In mitochondria, p13 produces an inward K+current that results in an increased production of ROS by mitochondria. These effects are linked to the protein’s effects on cell turnover which include activation of primary T-cells and reduced proliferation/sensitization to death of tumor cells. Recent findings suggest that in the presence of Tax, p13 is subjected to ubiquitylation and partly targeted to the nucleus. Nuclear p13 binds Tax and inhibits its transcriptional activity. These findings suggest that the protein might exert distinct functions depending on its intracellular localization and influence both the turnover of infected cells and the balance between viral latency and productive infection. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
44. The p13 protein of human T cell leukemia virus type 1 (HTLV-1) modulates mitochondrial membrane potential and calcium uptake
- Author
-
Biasiotto, Roberta, Aguiari, Paola, Rizzuto, Rosario, Pinton, Paolo, D'Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
- *
MITOCHONDRIAL membranes , *HTLV-I , *MEMBRANE proteins , *CALCIUM channels , *HOMEOSTASIS , *POTASSIUM channels , *CELLULAR signal transduction - Abstract
Abstract: Human T cell leukemia virus type 1 (HTLV-1) encodes p13, an 87-amino-acid protein that accumulates in the inner mitochondrial membrane. Recent studies performed using synthetic p13 and isolated mitochondria demonstrated that the protein triggers an inward potassium (K+) current and inner membrane depolarization. The present study investigated the effects of p13 on mitochondrial inner membrane potential (Δψ) in living cells. Using the potential-dependent probe tetramethyl rhodamine methyl ester (TMRM), we observed that p13 induced dose-dependent mitochondrial depolarization in HeLa cells. This effect was abolished upon mutation of 4 arginines in p13''s α-helical domain that were previously shown to be essential for its activity in in vitro assays. As Δψ is known to control mitochondrial calcium (Ca2+) uptake, we next analyzed the effect of p13 on Ca2+ homeostasis. Experiments carried out in HeLa cells expressing p13 and organelle-targeted aequorins revealed that the protein specifically reduced mitochondrial Ca2+ uptake. These observations suggest that p13 might control key processes regulated through Ca2+ signaling such as activation and death of T cells, the major targets of HTLV-1 infection. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
45. Modulation of mitochondrial K+ permeability and reactive oxygen species production by the p13 protein of human T-cell leukemia virus type 1
- Author
-
Silic-Benussi, Micol, Cannizzaro, Enrica, Venerando, Andrea, Cavallari, Ilaria, Petronilli, Valeria, La Rocca, Nicoletta, Marin, Oriano, Chieco-Bianchi, Luigi, Di Lisa, Fabio, D'Agostino, Donna M., Bernardi, Paolo, and Ciminale, Vincenzo
- Subjects
- *
VIRAL proteins , *HTLV , *PERMEABILITY , *GENE expression , *REACTIVE oxygen species , *POTASSIUM channels , *HYDROGEN-ion concentration , *BIOLOGICAL assay - Abstract
Abstract: Human T-cell leukemia virus type-1 (HTLV-1) expresses an 87-amino acid protein named p13 that is targeted to the inner mitochondrial membrane. Previous studies showed that a synthetic peptide spanning an alpha helical domain of p13 alters mitochondrial membrane permeability to cations, resulting in swelling. The present study examined the effects of full-length p13 on isolated, energized mitochondria. Results demonstrated that p13 triggers an inward K+ current that leads to mitochondrial swelling and confers a crescent-like morphology distinct from that caused by opening of the permeability transition pore. p13 also induces depolarization, with a matching increase in respiratory chain activity, and augments production of reactive oxygen species (ROS). These effects require an intact alpha helical domain and strictly depend on the presence of K+ in the assay medium. The effects of p13 on ROS are mimicked by the K+ ionophore valinomycin, while the protonophore FCCP decreases ROS, indicating that depolarization induced by K+ vs. H+ currents has different effects on mitochondrial ROS production, possibly because of their opposite effects on matrix pH (alkalinization and acidification, respectively). The downstream consequences of p13-induced mitochondrial K+ permeability are likely to have an important influence on the redox state and turnover of HTLV-1-infected cells. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
46. Mitochondrial reactive oxygen species prime T-cell acute lymphoblastic leukemia to cell death by engaging the OMA1-OPA1 axis.
- Author
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Silic-Benussi, Micol, Scattolin, Gloria, Cavallari, Ilaria, Minuzzo, Sonia, Basso, Giuseppe, Indraccolo, Stefano, D’Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
- *
REACTIVE oxygen species , *T cells , *LEUKEMIA , *CELL death , *CELL lines - Published
- 2016
- Full Text
- View/download PDF
47. Control of ROS production and T-cell turnover by the p13 protein of HTLV-1
- Author
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Silic-Benussi, Micol, Cavallari, Ilaria, Chieco-Bianchi, Luigi, di Lisa, Fabio, D'Agostino, Donna M., and Ciminale, Vincenzo
- Published
- 2010
- Full Text
- View/download PDF
48. S10.8 Remodelling of mitochondrial function by the p13 protein of HTLV-1: Effects on reactive oxygen species and cell death
- Author
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Silic-Benussi, Micol, Cannizzaro, Enrica, Vajente, Nicola, Rende, Francesca, Chieco-Bianchi, Luigi, Saggioro, Daniela, Di Lisa, Fabio, D'Agostino, Donna M., Bernardi, Paolo, and Ciminale, Vincenzo
- Published
- 2008
- Full Text
- View/download PDF
49. mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells.
- Author
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Silic-Benussi M, Sharova E, Ciccarese F, Cavallari I, Raimondi V, Urso L, Corradin A, Kotler H, Scattolin G, Buldini B, Francescato S, Basso G, Minuzzo SA, Indraccolo S, D'Agostino DM, and Ciminale V
- Subjects
- Animals, Apoptosis, Cell Line, Tumor, Dexamethasone pharmacology, Dexamethasone therapeutic use, Everolimus pharmacology, Everolimus therapeutic use, Glucosephosphate Dehydrogenase genetics, Glucosephosphate Dehydrogenase metabolism, Humans, MTOR Inhibitors, Mice, Mice, Inbred NOD, Mice, SCID, NADP, Reactive Oxygen Species metabolism, T-Lymphocytes metabolism, TOR Serine-Threonine Kinases metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
mTOR activation is a hallmark of T-cell acute lymphoblastic leukemia (T-ALL) and is associated with resistance to glucocorticoid (GC)-based chemotherapy. We previously showed that altering redox homeostasis primes T-ALL cells to GC-induced apoptosis. Here we investigated the connection between the mTOR pathway and redox homeostasis using pharmacological inhibitors and gene silencing. In vitro studies performed on T-ALL cell lines and CG-resistant patient-derived T-ALL xenograft (PDX) cells showed that the mTOR inhibitor everolimus increased reactive oxygen species (ROS) levels, augmented lipid peroxidation, and activated the ROS-controlled transcription factor NRF2. These effects were accompanied by a decrease in the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), which is a major source of cytosolic NADPH needed for maintaining the cellular ROS-scavenging capacity. The mTOR inhibitor everolimus induced mitochondrial inner membrane depolarization and dose-dependent apoptosis of T-ALL cells, but did not kill normal T-cells. Importantly, the combination of everolimus and the GC dexamethasone had a synergistic effect on killing T-ALL cells. The effects of mTOR inhibition were blunted by ROS scavengers and phenocopied by siRNA-mediated G6PD silencing. In vivo studies of NOD/SCID mice inoculated with refractory T-ALL PDX demonstrated that everolimus overcame dexamethasone resistance in conditions of high tumor burden that mimicked the clinical setting of acute leukemia. These findings provide insight into the crosstalk between mTOR and ROS homeostasis in T-ALL cells and furnish mechanistic evidence to support the combination of glucocorticoids with mTOR inhibitors as a therapeutic avenue for treating refractory T-ALL., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
50. Expression of miR-34a in T-Cells Infected by Human T-Lymphotropic Virus 1.
- Author
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Sharma VK, Raimondi V, Ruggero K, Pise-Masison CA, Cavallari I, Silic-Benussi M, Ciminale V, and D'Agostino DM
- Abstract
Human T-lymphotropic virus 1 (HTLV-1) immortalizes T-cells and is the causative agent of adult T-cell leukemia/lymphoma (ATLL). HTLV-1 replication and transformation are governed by multiple interactions between viral regulatory proteins and host cell factors that remain to be fully elucidated. The present study investigated the impact of HTLV-1 infection on the expression of miR-34a, a microRNA whose expression is downregulated in many types of cancer. Results of RT-PCR assays showed that five out of six HTLV-1-positive cell lines expressed higher levels of miR-34a compared to normal PBMC or purified CD4+ T-cells. ATLL cell line ED, which did not express miR-34a, showed methylation of the miR-34a promoter. Newly infected PBMC and samples from 10 ATLL patients also showed a prominent increase in miR-34a expression compared to PBMC controls. The primary miR-34a transcript expressed in infected cell line C91PL contained binding motifs for NF-κB and p53. Pharmacological inhibition of NF-κB with Bay 11-7082 indicated that this pathway contributes to sustain miR-34a levels in infected cells. Treatment of infected cell lines with the p53 activator nutlin-3a resulted in a further increase in miR-34a levels, thus confirming it as a transcriptional target of p53. Nutlin-3a-treated cells showed downregulation of known miR-34a targets including the deacetylase SIRT1, which was accompanied by increased acetylation of p53, a substrate of SIRT1. Transfection of C91PL cells with a miR-34a mimic also led to downregulation of mRNA targets including SIRT1 as well as the pro-apoptotic factor BAX. Unlike nutlin-3a, the miR-34a mimic did not cause cell cycle arrest or reduce cell viability. On the other hand, sequestration of miR-34a with a sponge construct resulted in an increase in death of C91PL cells. These findings provide evidence for a functional role for miR-34a in fine-tuning the expression of target genes that influence the turnover of HTLV-1-infected cells.
- Published
- 2018
- Full Text
- View/download PDF
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