11 results on '"D'Agostino, Donna M."'
Search Results
2. MiR-150 in HTLV-1 infection and T-cell transformation.
- Author
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D'Agostino, Donna M., Raimondi, Vittoria, Silic-Benussi, Micol, and Ciminale, Vincenzo
- Subjects
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]
- Published
- 2022
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- View/download PDF
3. Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue.
- Author
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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]
- Published
- 2019
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4. Mitochondrial Proteins Coded by Human Tumor Viruses.
- Author
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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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5. Identification of novel monocistronic HTLV-1 mRNAs encoding functional Rex isoforms.
- Author
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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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HTLV-I ,MESSENGER RNA ,RETROVIRUS genetics ,GENETIC regulation ,HTLV-I infections ,GENETICS ,VIRUSES - Abstract
Background: Human T cell leukemia virus type 1 (HTLV-1) gene expression is controlled by the key regulatory proteins Tax and Rex. The concerted action of these proteins results in a two-phase kinetics of viral expression that depends on a time delay between their action. However, it is difficult to explain this delay, as Tax and Rex are produced from the same mRNA. In the present study we investigated whether HTLV-1 may produce novel mRNA species capable of expressing Rex and Tax independently. Findings: Results revealed the expression of three alternatively spliced transcripts coding for novel Rex isoforms in infected cell lines and in primary samples from infected patients. One mRNA coded for a Tax isoform and a Rex isoform, and two mRNAs coded for Rex isoforms but not Tax. Functional assays showed that these Rex isoforms exhibit activity comparable to canonic Rex. An analysis of the temporal expression of these transcripts upon ex vivo culture of cells from infected patients and cell lines transfected with a molecular clone of HTLV-1 revealed early expression of the dicistronic tax/rex mRNAs followed by the monocistronic mRNAs coding for Rex isoforms. Conclusion: The production of monocistronic HTLV-1 mRNAs encoding Rex isoforms with comparable activity to canonical Rex, but with distinct timing, would support a prolonged duration of Rex function with gradual loss of Tax, and is consistent with the two-phase expression kinetics. A thorough understanding of these regulatory circuits will shed light on the basis of viral latency and provide groundwork to develop strategies for eradicating persistent infections. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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6. 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]
- Published
- 2011
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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?
- Author
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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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8. NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ.
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Fochi, Stefania, Ciminale, Vincenzo, Trabetti, Elisabetta, Bertazzoni, Umberto, D'Agostino, Donna M., Zipeto, Donato, and Romanelli, Maria Grazia
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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]
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- 2019
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9. HTLV-1 p13, a small protein with a busy agenda
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Silic-Benussi, Micol, Biasiotto, Roberta, Andresen, Vibeke, Franchini, Genoveffa, D’Agostino, Donna M., and Ciminale, Vincenzo
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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
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10. 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.
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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
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11. The p13 protein of human T cell leukemia virus type 1 (HTLV-1) modulates mitochondrial membrane potential and calcium uptake
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Biasiotto, Roberta, Aguiari, Paola, Rizzuto, Rosario, Pinton, Paolo, D'Agostino, Donna M., and Ciminale, Vincenzo
- Subjects
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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
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