137 results on '"Ciccosanti F"'
Search Results
2. Applying proteomic technology to clinical virology
- Author
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Mancone, C., Ciccosanti, F., Montaldo, C., Perdomo, A.B., Piacentini, M., Alonzi, T., Fimia, G.M., and Tripodi, M.
- Published
- 2013
- Full Text
- View/download PDF
3. Analysis of Secreted Proteins from Prepubertal Ovarian Tissues Exposed In Vitro to Cisplatin and LH
- Author
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Marcozzi, S., Ciccosanti, F., Fimia, G. M., Piacentini, M., Caggiano, C., Sette, C., De Felici, M., Klinger, F. G., Caggiano C., Sette C. (ORCID:0000-0003-2864-8266), Marcozzi, S., Ciccosanti, F., Fimia, G. M., Piacentini, M., Caggiano, C., Sette, C., De Felici, M., Klinger, F. G., Caggiano C., and Sette C. (ORCID:0000-0003-2864-8266)
- Abstract
It is well known that secreted and exosomal proteins are associated with a broad range of physiological processes involving tissue homeostasis and differentiation. In the present paper, our purpose was to characterize the proteome of the culture medium in which the oocytes within the primordial/primary follicles underwent apoptosis induced by cisplatin (CIS) or were, for the most part, protected by LH against the drug. To this aim, prepubertal ovarian tissues were cultured under control and in the presence of CIS, LH, and CIS + LH. The culture media were harvested after 2, 12, and 24 h from chemotherapeutic drug treatment and analyzed by liquid chromatography–mass spectrometry (LC-MS). We found that apoptotic conditions generated by CIS in the cultured ovarian tissues and/or oocytes are reflected in distinct changes in the extracellular microenvironment in which they were cultured. These changes became evident mainly from 12 h onwards and were characterized by the inhibition or decreased release of a variety of compounds, such as the proteases Htra1 and Prss23, the antioxidants Prdx2 and Hbat1, the metabolic regulators Ldha and Pkm, and regulators of apoptotic pathways such as Tmsb4x. Altogether, these results confirm the biological relevance of the LH action on prepuberal ovaries and provide novel information about the proteins released by the ovarian tissues exposed to CIS and LH in the surrounding microenvironment. These data might represent a valuable resource for future studies aimed to clarify the effects and identify biomarkers of these compounds’ action on the developing ovary.
- Published
- 2022
4. The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells
- Author
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Cappellari, M, Bielli, P, Paronetto, M P, Ciccosanti, F, Fimia, G M, Saarikettu, J, Silvennoinen, O, and Sette, C
- Published
- 2014
- Full Text
- View/download PDF
5. Mitochondrial interactome: a focus on antiviral signaling pathways
- Author
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Refolo, G, Vescovo, T, nbsp, Piacentini, M, Fimia, G, and Ciccosanti, F
- Subjects
Settore BIO/06 - Published
- 2020
6. Bcl-2 inhibits the caspase-dependent apoptosis induced by SARS-CoV without affecting virus replication kinetics
- Author
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Bordi, L., Castilletti, C., Falasca, L., Ciccosanti, F., Calcaterra, S., Rozera, G., Di Caro, A., Zaniratti, S., Rinaldi, A., Ippolito, G., Piacentini, M., and Capobianchi, M. R.
- Published
- 2006
- Full Text
- View/download PDF
7. Persistence of chronic premature priming for apoptosisin HIV-infected individuals during HAART and short structured interruption: P673
- Author
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Amendola, A., DʼOffizi, G., Ciccosanti, F., Narciso, P., Capobianchi, M. R., Poccia, F., Ippolito, G., and Piacentini, M.
- Published
- 2005
8. Expression of Werner and Bloom syndrome genes is differentially regulated by in vitro HIV-1 infection of peripheral blood mononuclear cells
- Author
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BORDI, L., AMENDOLA, A., CICCOSANTI, F., ABBATE, I., CAMILLONI, G., and CAPOBIANCHI, M. R.
- Published
- 2004
9. Negative regulation of MAVS-mediated antiviral signaling by the mitochondrial protein LRPPRC during HCV infection
- Author
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Refolo, G, Ciccosanti, F, DI RIENZO, M, Perdomo, A, Romani, M, Alonzi, T, Tripodi, M, Ippolito, G, Piacentini, M, and Fimia, G
- Subjects
HCV NS5A ,Interferon Response ,Proteomics ,Settore BIO/06 ,interferon response ,mitochondrial immunity ,proteomics ,Mitochondrial Immunity - Published
- 2018
10. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains
- Author
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Di Rienzo, M., primary, Antonioli, M., additional, Fusco, C., additional, Liu, Y., additional, Mari, M., additional, Orhon, I., additional, Refolo, G., additional, Germani, F., additional, Corazzari, M., additional, Romagnoli, A., additional, Ciccosanti, F., additional, Mandriani, B., additional, Pellico, M. T., additional, De La Torre, R., additional, Ding, H., additional, Dentice, M., additional, Neri, M., additional, Ferlini, A., additional, Reggiori, F., additional, Kulesz-Martin, M., additional, Piacentini, M., additional, Merla, G., additional, and Fimia, G. M., additional
- Published
- 2019
- Full Text
- View/download PDF
11. AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis
- Author
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Becher, J., Simula, L., Volpe, E., Procaccini, C., La Rocca, C., D'Acunzo, P., Cianfanelli, V., Strappazzon, F., Caruana, I., Nazio, F., Weber, G., Gigantino, V., Botti, G., Ciccosanti, F., Borsellino, G., Campello, S., Mandolesi, G., De Bardi, M., Fimia, G. M., D'Amelio, M., Ruffini, F., Furlan, R., Centonze, D., Martino, G., Braghetta, P., Chrisam, M., Bonaldo, P., Matarese, G., Locatelli, Franco, Battistini, L., Cecconi, F., Locatelli F. (ORCID:0000-0002-7976-3654), Becher, J., Simula, L., Volpe, E., Procaccini, C., La Rocca, C., D'Acunzo, P., Cianfanelli, V., Strappazzon, F., Caruana, I., Nazio, F., Weber, G., Gigantino, V., Botti, G., Ciccosanti, F., Borsellino, G., Campello, S., Mandolesi, G., De Bardi, M., Fimia, G. M., D'Amelio, M., Ruffini, F., Furlan, R., Centonze, D., Martino, G., Braghetta, P., Chrisam, M., Bonaldo, P., Matarese, G., Locatelli, Franco, Battistini, L., Cecconi, F., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Regulatory T cells (T reg ) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of T reg cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human T reg differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating T reg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis. Regulatory T cells (T reg ) maintain immunological tolerance and help control autoimmune disease susceptibility. Becher et al. show pro-autophagy factor AMBRA1 regulates human and mouse T reg differentiation and maintenance. AMBRA1 is upregulated in stimulated T cells to stabilize FOXO3 and has a protective effect in a mouse model of multiple sclerosis.
- Published
- 2018
12. Methods to Study the BECN1 Interactome in the Course of Autophagic Responses
- Author
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manuela antonioli, Ciccosanti F, Dengjel J, and Gm, Fimia
- Subjects
Tandem Mass Spectrometry ,Isotope Labeling ,Protein Interaction Mapping ,Autophagy ,Humans ,Beclin-1 ,Cell Line ,Chromatography, Liquid - Abstract
Autophagy is an extremely dynamic process that mediates the rapid degradation of intracellular components in response to different stress conditions. The autophagic response is executed by specific protein complexes, whose function is regulated by posttranslational modifications and interactions with positive and negative regulators. A comprehensive analysis of how autophagy complexes are temporally modified upon stress stimuli is therefore particularly relevant to understand how this pathway is regulated. Here, we describe a method to define the protein-protein interaction network of a central complex involved in autophagy induction, the Beclin 1 complex. This method is based on the quantitative comparison of protein complexes immunopurified at different time points using a stable isotope labeling by amino acids in cell culture approach. Understanding how the Beclin 1 complex dynamically changes in response to different stress stimuli may provide useful insights to disclose novel molecular mechanisms responsible for the dysregulation of autophagy in pathological conditions, such as cancer, neurodegeneration, and infections.
- Published
- 2017
13. Role of autophagy in HIV infection and pathogenesis
- Author
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Nardacci, R., primary, Ciccosanti, F., additional, Marsella, C., additional, Ippolito, G., additional, Piacentini, M., additional, and Fimia, G. M., additional
- Published
- 2017
- Full Text
- View/download PDF
14. Inhibition of autophagy in EBV-positive Burkitt's lymphoma cells enhances EBV lytic genes expression and replication
- Author
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DE LEO, Alessandra, Colavita, Francesca, Ciccosanti, F., Fimia, Gm, Lieberman, Pm, Mattia, Elena, Fimia, Gian Maria, De Leo, A, Colavita, F, Ciccosanti, F, Fimia, Gian Maria, Lieberman, P. M, and Mattia, E.
- Subjects
DNA Replication ,Cancer Research ,Programmed cell death ,Immunology ,Immunoblotting ,Cellular homeostasis ,Gene Expression ,Biology ,ciclo litico ,medicine.disease_cause ,Virus Replication ,Virus ,Cellular and Molecular Neuroscience ,linfomi ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Autophagy ,Humans ,Epstein Barr Virus ,autofagia ,epstein barr virus ,Cell Biology ,autophagy ,lytic cycle ,Epstein–Barr virus ,Burkitt Lymphoma ,Oncolytic virus ,Cell biology ,Lytic cycle ,Viral replication ,Original Article - Abstract
Autophagy, an important degradation system involved in maintaining cellular homeostasis, serves also to eliminate pathogens and process their fragments for presentation to the immune system. Several viruses have been shown to interact with the host autophagic machinery to suppress or make use of this cellular catabolic pathway to enhance their survival and replication. Epstein Barr virus (EBV) is a γ-herpes virus associated with a number of malignancies of epithelial and lymphoid origin in which establishes a predominantly latent infection. Latent EBV can periodically reactivate to produce infectious particles that allow the virus to spread and can lead to the death of the infected cell. In this study, we analyzed the relationship between autophagy and EBV reactivation in Burkitt’s lymphoma cells. By monitoring autophagy markers and EBV lytic genes expression, we demonstrate that autophagy is enhanced in the early phases of EBV lytic activation but decreases thereafter concomitantly with increased levels of EBV lytic proteins. In a cell line defective for late antigens expression, we found an inverse correlation between EBV early antigens expression and autophagosomes formation, suggesting that early after activation, the virus is able to suppress autophagy. We report here for the first time that inhibition of autophagy by Bafilomycin A1 or shRNA knockdown of Beclin1 gene, highly incremented EBV lytic genes expression as well as intracellular viral DNA and viral progeny yield. Taken together, these findings indicate that EBV activation induces the autophagic response, which is soon inhibited by the expression of EBV early lytic products. Moreover, our findings open the possibility that pharmacological inhibitors of autophagy may be used to enhance oncolytic viral therapy of EBV-related lymphomas.
- Published
- 2015
15. Il ciclo litico di EBV e la risposta autofagica in cellule di linfoma di Burkitt
- Author
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Colavita, F., DE LEO, Alessandra, Ciccosanti, F., Fimia, G. M., and Mattia, Elena
- Subjects
EBV - Published
- 2013
16. An immunosurveillance mechanism controls cancer cell ploidy
- Author
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Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, Galluzzi L, Adjemian S, Kepp O, Niso-Santano M, Shen S, Marixf1o G, Criollo A, Boilxe8ve A, Job B, Ladoire S, Ghiringhelli F, Sistigu A, Yamazaki T, Rello-Varona S, Locher C, Poirier-Colame V, Talbot M, Valent A, Berardinelli F, Antoccia A, Ciccosanti F, Fimia GM, Piacentini M, Fueyo A, Messina NL, Li M, Chan CJ, Sigl V, Pourcher G, Ruckenstuhl C, Carmona-Gutierrez D, Lazar V, Penninger JM, Madeo F, Lxf3pez-Otxedn C, Smyth MJ, Zitvogel L, and Castedo
- Published
- 2012
17. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma
- Author
-
Corazzari, M, primary, Rapino, F, additional, Ciccosanti, F, additional, Giglio, P, additional, Antonioli, M, additional, Conti, B, additional, Fimia, G M, additional, Lovat, P E, additional, and Piacentini, M, additional
- Published
- 2014
- Full Text
- View/download PDF
18. Protective role of bcl-2 in the induction of cytopathic effect and of apoptotic cell death in SARS-CoV-infected VERO cells, in the absence of inhibition of viral replication
- Author
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Castilletti, C, Ciccosanti, F, Calcaterra, S, Bordi, L, Falasca, L, Rozera, G, Di Caro, A, Zaniratti, S, Ippolito, G, Piacentini, M, and Capobianchi, MR
- Subjects
ddc: 610 - Published
- 2004
19. Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
- Author
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Vakifahmetoglu-Norberg, H, primary, Norberg, E, additional, Perdomo, A B, additional, Olsson, M, additional, Ciccosanti, F, additional, Orrenius, S, additional, Fimia, G M, additional, Piacentini, M, additional, and Zhivotovsky, B, additional
- Published
- 2013
- Full Text
- View/download PDF
20. Transglutaminase overexpression sensitizes neuronal cell lines to apoptosis by increasing mitochondrial membrane potential and cellular oxidative stress
- Author
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Piacentini, M, Farrace, Mg, Piredda, L, Matarrese, P, Ciccosanti, F, Falasca, L, Rodolfo, C, Giammarioli, A, Verderio, E, Griffin, M, and Malorni, W
- Subjects
Settore BIO/06 ,Gene Expression ,Apoptosis ,Transfection ,Mitochondrial Membrane Transport Proteins ,Ion Channels ,Membrane Potentials ,Neuroblastoma ,Mice ,GTP-Binding Proteins ,Animals ,Humans ,Enzyme Inhibitors ,3T3 Cells ,Oxidative Stress ,Cyclosporine ,Tetracycline ,Mitochondria ,Intracellular Membranes ,Flow Cytometry ,Transglutaminases ,Tumor Cells, Cultured ,Neurons ,Child ,Oxidation-Reduction ,Cultured ,Tumor Cells - Published
- 2002
21. Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response
- Author
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Pagliarini, Vittoria, Wirawan, E., Romagnoli, A., Ciccosanti, F., Lisi, G., Lippens, S., Cecconi, F., Fimia, G. M., Vandenabeele, P., Corazzari, M., Piacentini, M., Pagliarini V. (ORCID:0000-0002-2388-0675), Pagliarini, Vittoria, Wirawan, E., Romagnoli, A., Ciccosanti, F., Lisi, G., Lippens, S., Cecconi, F., Fimia, G. M., Vandenabeele, P., Corazzari, M., Piacentini, M., and Pagliarini V. (ORCID:0000-0002-2388-0675)
- Abstract
Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program. © 2012 Macmillan Publishers Limited All rights reserved.
- Published
- 2012
22. The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage
- Author
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De Zio, D., Bordi, M., Tino, E., Lanzuolo, C., Ferraro, E., Mora, E., Ciccosanti, F., Fimia, G. M., Orlando, V., Cecconi, F., De Zio, D., Bordi, M., Tino, E., Lanzuolo, C., Ferraro, E., Mora, E., Ciccosanti, F., Fimia, G. M., Orlando, V., and Cecconi, F.
- Abstract
Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, as it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and downregulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a downregulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 upregulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival.
- Published
- 2011
23. Proteomic analysis identifies prohibitin down-regulation as a crucial event in the mitochondrial damage observed in HIV-infected patients
- Author
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Ciccosanti, F., Corazzari, M., Soldani, F., Matarrese, P., Pagliarini, V., Iadevaia, V., Tinari, A., Zaccarelli, M., Perfettini, J. -L., Malorni, W., Kroemer, G., Antinori, A., Fimia, G. M., Piacentini, M., Pagliarini V. (ORCID:0000-0002-2388-0675), Ciccosanti, F., Corazzari, M., Soldani, F., Matarrese, P., Pagliarini, V., Iadevaia, V., Tinari, A., Zaccarelli, M., Perfettini, J. -L., Malorni, W., Kroemer, G., Antinori, A., Fimia, G. M., Piacentini, M., and Pagliarini V. (ORCID:0000-0002-2388-0675)
- Abstract
Background: Highly active antiretroviral therapy (HAART) has largely reduced the occurrence of AIDS-related diseases and death in HIV-infected patients. However, HAART produces serious side effects mainly attributed to mitochondrial toxicity. Methods: To elucidate the molecular basis of HAART-related dysfunctions, we analysed the mitochondrial proteome of peripheral blood mononuclear cells from HIV-infected patients using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analysis was performed on HIV patients who were either treatment- naive or under HAART therapy including zidovudine or stavudine as nucleoside reverse transcriptase inhibitors (NRTIs). Results: As compared to healthy donors, HAART-treated HIV-infected patients exhibited decreased levels of mitochondrial enzymes associated with energy production as well as mitochondrial chaperones. Moreover, significant alterations in the mitochondria-cytoskeleton network were observed. Notably, most of these changes were already detectable in untreated HIV carriers and persisted or worsened after HAART, indicating that relevant mitochondrial alterations were initially caused by HIV infection. Finally, in vitro experiments aimed at validating the proteomic results showed that down-regulation of the mitochondrial chaperone prohibitin is a causative event in NRTI-induced mitochondrial damage. Conclusions: Our results indicate a major role of HIV infection in the mitochondrial toxicity of HAART-treated patients and identify novel candidate markers for assessing the risk of HIV- and HAART-related pathologies. ©2010 International Medical Press.
- Published
- 2010
24. The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells
- Author
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Cappellari, M, primary, Bielli, P, additional, Paronetto, M P, additional, Ciccosanti, F, additional, Fimia, G M, additional, Saarikettu, J, additional, Silvennoinen, O, additional, and Sette, C, additional
- Published
- 2013
- Full Text
- View/download PDF
25. Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response
- Author
-
Pagliarini, V, primary, Wirawan, E, additional, Romagnoli, A, additional, Ciccosanti, F, additional, Lisi, G, additional, Lippens, S, additional, Cecconi, F, additional, Fimia, G M, additional, Vandenabeele, P, additional, Corazzari, M, additional, and Piacentini, M, additional
- Published
- 2012
- Full Text
- View/download PDF
26. The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage
- Author
-
De Zio, D, primary, Bordi, M, additional, Tino, E, additional, Lanzuolo, C, additional, Ferraro, E, additional, Mora, E, additional, Ciccosanti, F, additional, Fimia, G M, additional, Orlando, V, additional, and Cecconi, F, additional
- Published
- 2010
- Full Text
- View/download PDF
27. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma.
- Author
-
Corazzari, M, Rapino, F, Ciccosanti, F, Giglio, P, Antonioli, M, Conti, B, Fimia, G M, Lovat, P E, and Piacentini, M
- Subjects
BRAF genes ,AUTOPHAGY ,APOPTOSIS ,MELANOMA ,ENDOPLASMIC reticulum ,CANCER cells ,CANCER invasiveness - Abstract
The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF
V600E mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAFV600E induces a chronic ER stress status directly increasing basal cell autophagy. BRAFV600E -mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAFV600E -mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAFV600E melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
28. Bcl-2 inhibits the caspase-dependent apoptosis induced by SARS-CoV without affecting virus replication kinetics
- Author
-
Bordi, L., primary, Castilletti, C., additional, Falasca, L., additional, Ciccosanti, F., additional, Calcaterra, S., additional, Rozera, G., additional, Di Caro, A., additional, Zaniratti, S., additional, Rinaldi, A., additional, Ippolito, G., additional, Piacentini, M., additional, and Capobianchi, M. R., additional
- Published
- 2005
- Full Text
- View/download PDF
29. Trying to catch the HCV virus in its ‘battle field’
- Author
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Falasca, L, primary, Ciccosanti, F, additional, Nardacci, R, additional, Antonucci, G, additional, and Piacentini, M, additional
- Published
- 2003
- Full Text
- View/download PDF
30. Type 2 Transglutaminase and Cell Death.
- Author
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Piacentini, M., Amendola, A., Ciccosanti, F., Falasca, L., Farrace, M., Mastroberardino, P., Nardacci, R., Oliverio, S., Piredda, L., Rodolfo, C., and Autuori, F.
- Published
- 2005
- Full Text
- View/download PDF
31. Expression of Werner and Bloom syndrome genes is differentially regulated byin vitroHIV-1 infection of peripheral blood mononuclear cells.
- Author
-
BORDI, L., AMENDOLA, A., CICCOSANTI, F., ABBATE, I., CAMILLONI, G., and CAPOBIANCHI, M. R.
- Subjects
HIV infections ,AGING ,MESSENGER RNA ,LENTIVIRUS diseases ,DNA polymerases ,POLYMERASE chain reaction - Abstract
In HIV infection, continuous immune activation leads to accelerated ageing of the adaptive immune system, similar to that observed in elderly people. We investigated the expression of WRN and BLM (genes involved in disorders characterized by premature ageing, genomic instability and cancer predisposition) in peripheral blood mononuclear cells (PBMC) activatedin vitrowith phytohaemagglutinin (PHA) and infected with different HIV-1 strains. The steady state levels of mRNA were analysed by reverse transcription-polymerase chain reaction (RT-PCR), and protein expression was assayed using immunocytochemistry and Western blot techniques. In uninfected PBMC, PHA stimulation induced an increase in BLM mRNA and protein expression, while WRN expression remained virtually unchanged. When PBMC were infectedin vitrowith a lymphotropic HIV-1 strain, the level of BLM mRNA showed a peak at 24 h of infection, followed by a decline to uninfected culture levels. A similar result failed to be seen using an R5-tropic HIV-1 strain. In accordance with mRNA expression, in HIV-infected cultures PBMC were stained more frequently and more intensely by a BLM-specific antibody as compared to uninfected cultures, staining peaking at 24. Conversely, WRN expression was not modulated by HIV-1. The proportion of cells showing BLM up-regulation, established by immunocytochemical staining, was much greater than the proportion of productively infected PBMC, as established by proviral DNA measurement. This result indicates that BLM up-regulation is probably a result of an indirect bystander cell effect. Activation of the BLM gene in infected PBMC suggests that premature ageing could be a further immunopathogenetic mechanism involved in HIV-induced immunodeficiency, and points to a possible new candidate target for innovative therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
32. Transglutaminase overexpression sensitizes neuronal cell lines to apoptosis by increasing mitochondrial membrane potential and cellular oxidative stress.
- Author
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Grazia Farrace, M., Piredda, L., Matarrese, P., Ciccosanti, F., Falasca, L., Rodolfo, C., Giammarioli, A.M., Verderio, E., Griffin, M., and Malorni, W.
- Subjects
TRANSGLUTAMINASES ,APOPTOSIS ,MITOCHONDRIAL membranes - Abstract
‘Tissue’ transglutaminase (tTG) selectively accumulates in cells undergoing apoptosis both in vivo and in vitro. Considering the central role played by mitochondria in apoptosis, we investigated the relationships existing amongst tTG expression, apoptosis and mitochondrial function. To this aim we studied the mechanisms of apoptosis in a neuronal cell line (SK-N-BE (2)) in which the tTG-expression was driven by a constitutive promoter. Furthermore, a tet-off inducible promoter was also used in 3T3 fibroblastic cells used as control. Both cell lines, when expressing tTG, appeared ‘sensitized’ to apoptosis. Strikingly, we found major differences in the morphological features of mitochondria among cell lines in the absence of apoptotic stimuli. In addition, these ultrastructural characteristics were associated with specific functional features: (i) constitutively hyperpolarized mitochondria and (ii) increased reactive oxygen intermediates production. Importantly, after mitochondrial-mediated apoptosis by stauro- sporine, a rapid loss of mitochondrial membrane potential was found in tTG cells only. Taken together, these results seem to suggest that, via hyperpolarization, tTG might act as a ‘sensitizer’ towards apoptotic stimuli specifically targeted to mitochondria. These results could also be of pathogenetic relevance for those diseases that are characterized by increased tTG and apoptotic rate together with impaired mitochondrial function, e.g. in some neurodegenerative disease. [ABSTRACT FROM AUTHOR]
- Published
- 2002
33. 'Tissue' transglutaminase expression in HIV-infected cells: An enzyme with an antiviral effect?
- Author
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Alessandra Amendola, Rodolfo, C., Caro, A. D. I., Ciccosanti, F., Falasca, L., and Piacentini, M.
34. Transglutaminase type II plays a protective role in hepatic injury
- Author
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Nardacci, R., Iacono, O. L., Ciccosanti, F., Falasca, L., Addesso, M., Amendola, A., Antonucci, G., Antonio Craxi, Fimia, G. M., Iadevaia, V., Melino, G., Ruco, L., Tocci, G., Ippolito, G., and Piacentini, M.
35. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains.
- Author
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Antonioli, M., Refolo, G., Germani, F., Romagnoli, A., Ciccosanti, F., Fimia, G. M., Di Rienzo, M., Piacentini, M., Fusco, C., Mandriani, B., Pellico, M. T., Merla, G., Liu, Y., De La Torre, R., Kulesz-Martin, M., Mari, M., Orhon, I., Reggiori, F., Corazzari, M., and Ding, H.
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AUTOPHAGY , *METABOLISM , *MUSCLE cells , *PATHOLOGY , *PHYSIOLOGY - Abstract
The article talks about autophagy, a catabolic process that removes excess or damaged cellular components in pathological and physiological conditions in addition to providing metabolic supplies in the event of scarcity of extracellular nutrients. Topics discussed include atrophic muscle cells based autophagy induction requiring ULK1 activation by TRIM32.
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- 2019
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36. Analysis of the periplasmic proteome of Pseudomonas aeruginosa, a metabolically versatile opportunistic pathogen
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Francesco Imperi, Paolo Visca, Fabiola Ciccosanti, Federica Tiburzi, Tonino Alonzi, Gian Maria Fimia, Carmine Mancone, Paolo Ascenzi, Ariel Basulto Perdomo, Mauro Piacentini, Imperi, F, Ciccosanti, F, Perdomo, Ab, Tiburzi, F, Mancone, C, Alonzi, T, Ascenzi, Paolo, Piacentini, M, Visca, Paolo, Fimia, Gm, Imperi, F., Ciccosanti, F., BASULTO PERDOMO, A., Tiburzi, F., Mancone, C., Alonsi, T., Ascenzi, P., Piacentini, M., and Fimia, G. M.
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Proteomics ,cell envelope ,Settore BIO/06 ,Virulence ,Biology ,Cell Fractionation ,medicine.disease_cause ,Biochemistry ,pseudomonas aeruginosa ,Microbiology ,Bacterial Proteins ,Protein Interaction Mapping ,medicine ,Electrophoresis, Gel, Two-Dimensional ,Molecular Biology ,periplasm ,Pseudomonas aeruginosa ,Periplasmic space ,2-de ,maldi-tof/tof ,biology.organism_classification ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Proteome ,bacteria ,Cell envelope ,Bacteria ,Pseudomonadaceae - Abstract
The Gram-negative bacterium Pseudomonas aeruginosa is a main cause of infection in hospitalized, burned, immunocompromised, and cystic fibrosis patients. Many processes essential for P. aeruginosa pathogenesis, e.g., nutrient uptake, antibiotic resistance, and virulence, take place in the cell envelope and depend on components residing in the periplasmic space. Recent high-throughput studies focused on P. aeruginosa membrane compartments. However, the composition and dynamics of its periplasm remain largely uncharacterized. Here, we report a detailed description of the periplasmic proteome of the wild-type P. aeruginosa strain PAO1 by 2-DE and MALDI-TOF/TOF analysis. Three extraction methods were compared at proteome level in order to achieve the most reliable and comprehensive periplasmic protein map. A total of 495 spots representing 395 different proteins were identified. Most of the high intensity spots corresponded to periplasmic proteins, while cytoplasmic contaminants were mainly detected among faint spots. The majority of the identified periplasmic proteins is involved in transport, cell-envelope integrity, and protein folding control. Notably, more than 30% still has an unpredicted function. This work provides the first overview of the P. aeruginosa periplasm and offers the basis for future studies on periplasmic proteome changes occurring during P. aeruginosa adaptation to different environments and/or antibiotic treatments.
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- 2009
37. Multi-omics approach to COVID-19: a domain-based literature review
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Chiara Montaldo, Francesco Messina, Isabella Abbate, Manuela Antonioli, Veronica Bordoni, Alessandra Aiello, Fabiola Ciccosanti, Francesca Colavita, Chiara Farroni, Saeid Najafi Fard, Emanuela Giombini, Delia Goletti, Giulia Matusali, Gabriella Rozera, Martina Rueca, Alessandra Sacchi, Mauro Piacentini, Chiara Agrati, Gian Maria Fimia, Maria Rosaria Capobianchi, Francesco Nicola Lauria, Giuseppe Ippolito, Montaldo, C., Messina, F., Abbate, I., Antonioli, M., Bordoni, V., Aiello, A., Ciccosanti, F., Colavita, F., Farroni, C., Najafi Fard, S., Giombini, E., Goletti, D., Matusali, G., Rozera, G., Rueca, M., Sacchi, A., Piacentini, M., Agrati, C., Fimia, G. M., Capobianchi, M. R., Lauria, F. N., and Ippolito, G.
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COVID-19 ,Conceptual domain ,Host signatures ,Omics ,Pathways ,Phenotypes ,SARS-CoV-2 ,Settore BIO/06 ,Pandemic ,General Medicine ,Review ,General Biochemistry, Genetics and Molecular Biology ,Immunity, Innate ,Phenotype ,Host signature ,Omic ,Medicine ,Humans ,Pandemics ,Pathway ,Human - Abstract
Background Omics data, driven by rapid advances in laboratory techniques, have been generated very quickly during the COVID-19 pandemic. Our aim is to use omics data to highlight the involvement of specific pathways, as well as that of cell types and organs, in the pathophysiology of COVID-19, and to highlight their links with clinical phenotypes of SARS-CoV-2 infection. Methods The analysis was based on the domain model, where for domain it is intended a conceptual repository, useful to summarize multiple biological pathways involved at different levels. The relevant domains considered in the analysis were: virus, pathways and phenotypes. An interdisciplinary expert working group was defined for each domain, to carry out an independent literature scoping review. Results The analysis revealed that dysregulated pathways of innate immune responses, (i.e., complement activation, inflammatory responses, neutrophil activation and degranulation, platelet degranulation) can affect COVID-19 progression and outcomes. These results are consistent with several clinical studies. Conclusions Multi-omics approach may help to further investigate unknown aspects of the disease. However, the disease mechanisms are too complex to be explained by a single molecular signature and it is necessary to consider an integrated approach to identify hallmarks of severity.
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- 2021
38. Transglutaminase 2 regulates innate immunity by modulating the STING/TBK1/IRF3 axis
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Alessandra Sacchi, Roberta Nardacci, Delia Goletti, Nick Barlev, Evgeni Smirnov, Ivana Palucci, Federica Rossin, Fabiola Ciccosanti, Gian Maria Fimia, Laura Falasca, Mauro Piacentini, Linda Petrone, Giovanni Delogu, Franca Del Nonno, Chiara Agrati, Maria Grazia Farrace, Manuela D’Eletto, Luca Occhigrossi, Occhigrossi, L., Rossin, F., D'Eletto, M., Farrace, M. G., Ciccosanti, F., Petrone, L., Sacchi, A., Nardacci, R., Falasca, L., Nonno, F. D., Palucci, I., Smirnov, E., Barlev, N., Agrati, C., Goletti, D., Delogu, G., Fimia, G. M., and Piacentini, M.
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Settore BIO/06 ,Protein Serine-Threonine Kinase ,Immunology ,Biology ,Protein Serine-Threonine Kinases ,type 2 transglutaminase ,inflammatory response ,STING ,03 medical and health sciences ,Mice ,0302 clinical medicine ,TANK-binding kinase 1 ,Immunity ,GTP-Binding Proteins ,Immunology and Allergy ,Animals ,Humans ,Protein Glutamine gamma Glutamyltransferase 2 ,Membrane Protein ,Mice, Knockout ,Innate immune system ,Transglutaminases ,Animal ,SARS-CoV-2 ,JAK-STAT signaling pathway ,Membrane Proteins ,COVID-19 ,Interferon-beta ,Transglutaminase ,Immunity, Innate ,Cell biology ,Sting ,Knockout mouse ,Phosphorylation ,Interferon Regulatory Factor-3 ,IRF3 ,030215 immunology ,GTP-Binding Protein ,Human ,Signal Transduction - Abstract
We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host’s inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow–derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1–IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19–positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.
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- 2021
39. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains
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Fulvio Reggiori, Monica Dentice, Marcella Neri, Manuela Antonioli, M. Di Rienzo, Idil Orhon, Fabiola Ciccosanti, Alessandra Ferlini, Giuseppe Merla, F. Germani, Mauro Piacentini, Barbara Mandriani, H. Ding, Giulia Refolo, Muriel Mari, Maria Teresa Pellico, Marco Corazzari, Molly Kulesz-Martin, Carmela Fusco, Gian Maria Fimia, Yuangang Liu, Alessandra Romagnoli, R. De La Torre, Center for Liver, Digestive and Metabolic Diseases (CLDM), Microbes in Health and Disease (MHD), Di Rienzo, M., Antonioli, M., Fusco, C., Liu, Y., Mari, M., Orhon, I., Refolo, G., Germani, F., Corazzari, M., Romagnoli, A., Ciccosanti, F., Mandriani, B., Pellico, M. T., De La Torre, R., Ding, H., Dentice, M., Neri, M., Ferlini, A., Reggiori, F., Kulesz-Martin, M., Piacentini, M., Merla, G., and Fimia, G. M.
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Plasma protein binding ,LS3_11 ,RNA, Small Interfering/metabolism ,Muscular Dystrophies ,Myoblasts ,Tripartite Motif Proteins ,Limb-Girdle ,Mice ,0302 clinical medicine ,Ubiquitin ,Myocyte ,Autophagy-Related Protein-1 Homolog ,Autophagy-Related Protein-1 Homolog/metabolism ,Research Articles ,adaptor proteins, signal transducing ,animals ,autophagy-related protein-1 homolog ,cell line ,cell transdifferentiation ,humans ,lysine ,mice ,mice, knockout ,muscular dystrophies, limb-girdle ,myoblasts ,protein binding ,rna interference ,rna, small interfering ,ubiquitin-protein ligases ,ubiquitination ,autophagy ,Mice, Knockout ,Muscular Dystrophies, Limb-Girdle/metabolism ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Signal transducing adaptor protein ,Adaptor Proteins ,SciAdv r-articles ,Muscle atrophy ,Ubiquitin ligase ,Cell biology ,030220 oncology & carcinogenesis ,RNA Interference ,medicine.symptom ,Research Article ,Signal Transduction ,Lysine/metabolism ,Protein Binding ,Settore BIO/06 ,Knockout ,Ubiquitin-Protein Ligases ,Ubiquitin-Protein Ligases/antagonists & inhibitors ,Small Interfering ,NO ,Cell Line ,03 medical and health sciences ,Adaptor Proteins, Signal Transducing/antagonists & inhibitors ,medicine ,Autophagy ,Animals ,Humans ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Lysine ,Signal Transducing ,Ubiquitination ,Cell Biology ,ULK1 ,Muscular Dystrophies, Limb-Girdle ,Cell Transdifferentiation ,biology.protein ,RNA ,RNA, Small Interfering ,Atrophy ,Myoblasts/cytology ,Transcription Factors - Abstract
Muscular dystrophy-associated mutations of TRIM32 impair ULK1-dependent autophagy response during muscle atrophy., Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32’s ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.
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- 2019
40. Role of autophagy in HIV infection and pathogenesis
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Gian Maria Fimia, Giuseppe Ippolito, Claudia Marsella, Roberta Nardacci, Fabiola Ciccosanti, Mauro Piacentini, Nardacci, R, Ciccosanti, F, Marsella, C, Ippolito, G, Piacentini, M, and Fimia, Gian Maria
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,Cell type ,autophagy ,Settore BIO/06 ,HIV ,cell death ,inflammation ,Autophagy-Related Proteins ,HIV Infections ,Biology ,Virus Replication ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Central Nervous System Infections ,Internal Medicine ,Bystander effect ,Autophagy ,Humans ,PI3K/AKT/mTOR pathway ,Immunity, Cellular ,Macrophages ,Dendritic Cells ,Acquired immune system ,Cell biology ,Chronic infection ,030104 developmental biology ,030217 neurology & neurosurgery - Abstract
The aim of autophagy is to re-establish homeostasis in response to a variety of stress conditions. By forming double-membrane vesicles, autophagy engulfs damaged or superfluous cytoplasmic material and recycles degradation products for new synthesis or energy production. Of note, the same mechanism is used to capture pathogens and has important implications in both innate and adaptive immunity. To establish a chronic infection, pathogens have therefore evolved multiple mechanisms to evade autophagy-mediated degradation. HIV infection represents one of the best characterized systems in which autophagy is disarmed by a virus using multiple strategies to prevent the sequestration and degradation of its proteins and to establish a chronic infection. HIV alters autophagy at various stages of the process in both infected and bystander cells. In particular, the HIV proteins TAT, NEF and ENV are involved in this regulation by either blocking or stimulating autophagy through direct interaction with autophagy proteins and/or modulation of the mTOR pathway. Although the roles of autophagy during HIV infection are multiple and vary amongst the different cell types, several lines of evidence point to a potential beneficial effect of stimulating autophagy-mediated lysosomal degradation to potentiate the immune response to HIV. Characterization of the molecular mechanisms regulating selective autophagy is expected to be valuable for developing new drugs able to specifically enhance the anti-HIV response.
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- 2017
41. Methods to Study the BECN1 Interactome in the Course of Autophagic Responses
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Fabiola Ciccosanti, Manuela Antonioli, Gian Maria Fimia, Jörn Dengjel, Antonioli, M, Ciccosanti, F, Dengjel, J, and Fimia, Gian Maria
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Proteomics ,0301 basic medicine ,Settore BIO/06 ,Interactome ,Immunoprecipitation ,Protein complexes ,Autophagic response ,Beclin 1 complex ,Mass spectrometry ,SILAC ,Biology ,03 medical and health sciences ,Stable isotope labeling by amino acids in cell culture ,medicine ,Autophagy ,Neurodegeneration ,Proteomic ,BECN1 ,medicine.disease ,Cell biology ,030104 developmental biology ,Protein complexe ,Function (biology) - Abstract
Autophagy is an extremely dynamic process that mediates the rapid degradation of intracellular components in response to different stress conditions. The autophagic response is executed by specific protein complexes, whose function is regulated by posttranslational modifications and interactions with positive and negative regulators. A comprehensive analysis of how autophagy complexes are temporally modified upon stress stimuli is therefore particularly relevant to understand how this pathway is regulated. Here, we describe a method to define the protein–protein interaction network of a central complex involved in autophagy induction, the Beclin 1 complex. This method is based on the quantitative comparison of protein complexes immunopurified at different time points using a stable isotope labeling by amino acids in cell culture approach. Understanding how the Beclin 1 complex dynamically changes in response to different stress stimuli may provide useful insights to disclose novel molecular mechanisms responsible for the dysregulation of autophagy in pathological conditions, such as cancer, neurodegeneration, and infections.
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- 2017
42. Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients
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Marzia Montalbano, Federico Martini, Federica Turchi, Gianpiero D'Offizi, Eleonora Cimini, Nicola Tumino, Gian Maria Fimia, Alessandra Sacchi, Veronica Bordoni, Chiara Agrati, Rita Casetti, Giulia Refolo, Chiara Taibi, Raffaella Lionetti, Fabiola Ciccosanti, Sacchi, A., Tumino, N., Turchi, F., Refolo, G., Fimia, G., Ciccosanti, F., Montalbano, M., Lionetti, R., Taibi, C., D'Offizi, G., Casetti, R., Bordoni, V., Cimini, E., Martini, F., and Agrati, C.
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0301 basic medicine ,antivirus agent ,Male ,CD86 protein ,Sustained Virologic Response ,medicine.medical_treatment ,B7 antigen ,Virus Replication ,Dendritic cells ,Telaprevir ,Polyethylene Glycols ,immunology ,chemistry.chemical_compound ,0302 clinical medicine ,oligopeptide ,middle aged ,T lymphocyte ,Immunology and Allergy ,macrogol derivative ,Directly acting antiviral ,Chronic ,IFN-α ,clinical article ,adult ,virus diseases ,Directly acting antivirals ,Phenotype ,Hepatitis C ,alpha interferon ,Hepatitis C virus genotype 1 ,Recombinant Proteins ,cell activation ,Up-Regulation ,aged ,female ,Treatment Outcome ,priority journal ,Combination ,HCV ,antiviral activity ,B7-1 Antigen ,cytokine production ,Drug Therapy, Combination ,030211 gastroenterology & hepatology ,Oligopeptides ,Dendritic cell ,medicine.drug ,combination drug therapy ,in vitro study ,ribavirin ,dendritic cell ,phenotype ,CD86 antigen ,peginterferon alpha2a ,telaprevir ,CD86 protein, human ,recombinant protein ,telaprevir, adult ,Article ,cell function ,controlled study ,drug potentiation ,flow cytometry ,hepatitis C ,human ,human cell ,male ,myeloid dendritic cell ,plasmacytoid dendritic cell ,treatment outcome ,upregulation ,virus replication ,chronic hepatitis C ,sustained virologic response, Aged ,Antiviral Agents ,B7-2 Antigen ,Dendritic Cells ,Female ,Hepatitis C, Chronic ,Humans ,Interferon-alpha ,Middle Aged ,Ribavirin ,T cells ,03 medical and health sciences ,Drug Therapy ,medicine ,CD86 ,Protease ,business.industry ,digestive system diseases ,In vitro ,030104 developmental biology ,chemistry ,Immunology ,business ,CD80 - Abstract
First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-α and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome. HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested. In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-α production by plasmacytoid DC, able to inhibit in vitro HCV replication.
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- 2017
43. An Immunosurveillance Mechanism Controls Cancer Cell Ploidy
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Guillermo Mariño, Frank Madeo, Lorenzo Galluzzi, Shensi Shen, Isabelle Martins, Alexander Valent, Bastien Job, Mark J. Smyth, Maria Castedo, Gian Maria Fimia, Mickaël Michaud, Francesco Berardinelli, Claire Pailleret, Alfredo Criollo, Vladimir Lazar, Santiago Rello-Varona, Guillaume Pourcher, Mauro Piacentini, Antonella Sistigu, Vichnou Poirier-Colame, Laura Senovilla, Sylvain Ladoire, Ming Li, Sandy Adjemian, Clara Locher, Ilio Vitale, Takahiro Yamazaki, Christoph Ruckenstuhl, Josef M. Penninger, Monique Talbot, Nicole L Messina, Antonio Antoccia, François Ghiringhelli, Verena Sigl, Fabiola Ciccosanti, Guido Kroemer, Mireia Niso-Santano, Maximilien Tailler, Oliver Kepp, Laurence Zitvogel, Alice Boilève, Carlos López-Otín, Didac Carmona-Gutierrez, Christopher J. Chan, Antonio Fueyo, Senovilla, L, Vitale, I, Martins, I, Tailler, M, Pailleret, C, Michaud, M, Galluzzi, L, Adjemian, S, Kepp, O, NISO SANTANO, M, Shen, S, Mariño, G, Criollo, A, Boilève, A, Job, B, Ladoire, S, Ghiringhelli, F, Sistigu, A, Yamazaki, T, RELLO VARONA, S, Locher, C, POIRIER COLAME, V, Talbot, M, Valent, A, Berardinelli, Francesco, Antoccia, Antonio, Ciccosanti, F, Fimia, Gm, Piacentini, M, Fueyo, A, Messina, Nl, Li, M, Chan, Cj, Sigl, V, Pourcher, G, Ruckenstuhl, C, CARMONA GUTIERREZ, D, Lazar, V, Penninger, Jm, Madeo, F, LÓPEZ OTÍN, C, Smyth, Mj, Zitvogel, L, Castedo, M, Kroemer, G., Senovilla, Laura, Vitale, Ilio, Martins, Isabelle, Tailler, Maximilien, Pailleret, Claire, Michaud, Mickaël, Galluzzi, Lorenzo, Adjemian, Sandy, Kepp, Oliver, Niso Santano, Mireia, Shen, Shensi, Mariño, Guillermo, Criollo, Alfredo, Boilève, Alice, Job, Bastien, Ladoire, Sylvain, Ghiringhelli, Françoi, Sistigu, Antonella, Yamazaki, Takahiro, Rello Varona, Santiago, Locher, Clara, Poirier Colame, Vichnou, Talbot, Monique, Valent, Alexander, Ciccosanti, Fabiola, Fimia, Gian Maria, Piacentini, Mauro, Fueyo, Antonio, Messina, Nicole L, Li, Ming, Chan, Christopher J, Sigl, Verena, Pourcher, Guillaume, Ruckenstuhl, Christoph, Carmona Gutierrez, Didac, Lazar, Vladimir, Penninger, Josef M, Madeo, Frank, López Otín, Carlo, Smyth, Mark J, Zitvogel, Laurence, Castedo, Maria, and Kroemer, Guido
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Settore BIO/06 ,Eukaryotic Initiation Factor-2 ,medicine.disease_cause ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Epigenetics ,Phosphorylation ,Endoplasmic Reticulum Stre ,Immunologic Surveillance ,Inbred BALB C ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Tumor ,Ploidies ,Multidisciplinary ,biology ,Animal ,Endoplasmic reticulum ,Cancer ,DNA, Neoplasm ,DNA ,Endoplasmic Reticulum Stress ,medicine.disease ,3. Good health ,Immunosurveillance ,Common Variable Immunodeficiency ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,biology.protein ,Cancer research ,Neoplasm ,Calreticulin ,Carcinogenesis ,Immunocompetence ,Human - Abstract
Keeping Cancer Cells At Bay Cancer cells are often aneuploid; that is, they have an abnormal number of chromosomes. But to what extent this contributes to the tumorigenic phenotype is not clear. Senovilla et al. (p. 1678 ; see the Perspective by Zanetti and Mahadevan ) found that tetraploidization of cancer cells can cause them to become immunogenic and thus aid in their clearance from the body by the immune system. Cells with excess chromosomes put stress on the endoplasmic reticulum, which leads to movement of the protein calreticulin to the cell surface. Calreticulin exposure in turn caused recognition of cancer cells in mice by the host immune system. Thus, the immune system appears to serve a protective role in eliminating hyperploid cells that must be overcome to allow unrestricted growth of cancer cells.
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- 2012
44. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma
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Gian Maria Fimia, Paola Giglio, B. Conti, Penny E. Lovat, Marco Corazzari, Mauro Piacentini, Francesca Rapino, Manuela Antonioli, Fabiola Ciccosanti, Corazzari, M, Rapino, F, Ciccosanti, F, Giglio, P, Antonioli, M, Conti, B, Fimia, Gian Maria, Lovat, P. E, and Piacentini, M.
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Proto-Oncogene Proteins B-raf ,Programmed cell death ,Settore BIO/06 ,Skin Neoplasms ,p38 mitogen-activated protein kinases ,Apoptosis ,Biology ,Lentiviru ,Cell Line, Tumor ,medicine ,Autophagy ,Humans ,ASK1 ,Endoplasmic Reticulum Stre ,Molecular Biology ,Melanoma ,PI3K/AKT/mTOR pathway ,Original Paper ,Lentivirus ,Apoptosi ,Cell Biology ,medicine.disease ,Endoplasmic Reticulum Stress ,Immunology ,Cutaneous melanoma ,Unfolded protein response ,Cancer research ,apoptosis ,autophagy ,cell line ,tumor ,endoplasmic reticulum stress ,humans ,lentivirus ,melanoma ,proto-oncogene proteins B-raf ,Human - Abstract
The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF(V600E) mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF(V600E) induces a chronic ER stress status directly increasing basal cell autophagy. BRAF(V600E)-mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF(V600E)-mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF(V600E) melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.
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- 2015
45. The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells
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Fabiola Ciccosanti, M. Cappellari, Claudio Sette, Olli Silvennoinen, Juha Saarikettu, Gian Maria Fimia, Maria Paola Paronetto, Pamela Bielli, Cappellari, M, Bielli, P, Paronetto, M. P, Ciccosanti, F, Fimia, Gian Maria, Saarikettu, J, Silvennoinen, O, and Sette, C.
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Male ,Cancer Research ,RNA-binding protein ,RNA-Binding Protein ,Exon ,Cell Movement ,CD44 ,Adaptor Proteins ,Signal Transducing ,Antigens ,Cell Line ,Tumor ,DNA-Binding Proteins ,Exons ,Gene Knockdown Techniques ,Humans ,Nuclear Proteins ,Prostatic Neoplasms ,Protein Binding ,RNA Polymerase II ,RNA-Binding Proteins ,Alternative Splicing ,Gene Expression Regulation ,Neoplastic ,Transcriptional Activation ,Nuclear Protein ,Settore BIO/16 ,Gene knockdown ,biology ,Antigens, CD44 ,Gene Expression Regulation, Neoplastic ,Hyaluronan Receptors ,RNA splicing ,Human ,Spliceosome ,DNA-Binding Protein ,Cell Line, Tumor ,Genetics ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Alternative splicing ,Endonucleases ,Gene Knockdown Technique ,Prostatic Neoplasm ,Cancer cell ,biology.protein ,Cancer research - Abstract
Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.
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- 2014
46. Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
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Sten Orrenius, Gian Maria Fimia, Helin Vakifahmetoglu-Norberg, Ariel Basulto Perdomo, Boris Zhivotovsky, Magnus Olsson, Fabiola Ciccosanti, Mauro Piacentini, E Norberg, Vakifahmetoglu Norberg, H, Norberg, E, Perdomo, Ab, Olsson, M, Ciccosanti, F, Orrenius, S, Fimia, Gian Maria, Piacentini, M, and Zhivotovsky, B.
- Subjects
caspase-2 ,Proteomics ,Cancer Research ,Proteases ,Settore BIO/06 ,DNA damage ,Immunology ,Caspase 2 ,Protein degradation ,Cellular and Molecular Neuroscience ,Tandem Mass Spectrometry ,Humans ,Electrophoresis, Gel, Two-Dimensional ,cytoskeleton protein ,Cytoskeleton ,Caspase ,biology ,Endoplasmic reticulum ,apoptosis ,Cell Biology ,Endoplasmic Reticulum Stress ,HCT116 Cells ,Cell biology ,Cysteine Endopeptidases ,Cytoskeletal Proteins ,Biochemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Proteome ,protein degradation ,biology.protein ,Original Article - Abstract
The caspase family of proteases cleaves large number of proteins resulting in major morphological and biochemical changes during apoptosis. Yet, only a few of these proteins have been reported to selectively cleaved by caspase-2. Numerous observations link caspase-2 to the disruption of the cytoskeleton, although it remains elusive whether any of the cytoskeleton proteins serve as bona fide substrates for caspase-2. Here, we undertook an unbiased proteomic approach to address this question. By differential proteome analysis using two-dimensional gel electrophoresis, we identified four cytoskeleton proteins that were degraded upon treatment with active recombinant caspase-2 in vitro. These proteins were degraded in a caspase-2-dependent manner during apoptosis induced by DNA damage, cytoskeleton disruption or endoplasmic reticulum stress. Hence, degradation of these cytoskeleton proteins was blunted by siRNA targeting of caspase-2 and when caspase-2 activity was pharmacologically inhibited. However, none of these proteins was cleaved directly by caspase-2. Instead, we provide evidence that in cells exposed to apoptotic stimuli, caspase-2 probed these proteins for proteasomal degradation. Taken together, our results depict a new role for caspase-2 in the regulation of the level of cytoskeleton proteins during apoptosis.
- Published
- 2013
47. Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response
- Author
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Gian Maria Fimia, Fabiola Ciccosanti, Marco Corazzari, Vittoria Pagliarini, Mauro Piacentini, Alessandra Romagnoli, Ellen Wirawan, Francesco Cecconi, Peter Vandenabeele, Saskia Lippens, G Lisi, Pagliarini, V, Wirawan, E, Romagnoli, A, Ciccosanti, F, Lisi, G, Lippens, S, Cecconi, F, Fimia, Gian Maria, Vandenabeele, P, Corazzari, M, and Piacentini, M.
- Subjects
autophagy ,Programmed cell death ,Settore BIO/06 ,Cell Survival ,Proteolysis ,Mutation, Missense ,Jurkat Cell ,Caspase 8 ,Jurkat Cells ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Adaptor Proteins ,Signal Transducing ,Amino Acid Substitution ,Apoptosis ,Autophagy ,Caspases ,Humans ,Mutation ,Missense ,medicine ,Molecular Biology ,Caspase ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Original Paper ,Settore BIO/11 - BIOLOGIA MOLECOLARE ,0303 health sciences ,Ambra1 ,apoptosis ,calpains ,caspases ,biology ,medicine.diagnostic_test ,Apoptosi ,Calpain ,Cell Biology ,Cell biology ,030220 oncology & carcinogenesis ,biology.protein ,Human - Abstract
Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program.
- Published
- 2012
48. The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage
- Author
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Valerio Orlando, Francesco Cecconi, Matteo Bordi, Fabiola Ciccosanti, Elisabetta Ferraro, Gian Maria Fimia, E Mora, D De Zio, Chiara Lanzuolo, E Tino, De Zio, D, Bordi, M, Tino, E, Lanzuolo, C, Ferraro, E, Mora, E, Ciccosanti, F, Fimia, Gian Maria, Orlando, V, Cecconi, F., and Dulbecco Telethon Institute/Department of Biology
- Subjects
Transcription, Genetic ,DNA Repair ,Response element ,Apoptosis ,Mice ,0302 clinical medicine ,transcriptional regulation ,Promoter Regions, Genetic ,Etoposide ,0303 health sciences ,Ku70 ,Cell Death ,Antigens, Nuclear ,DNA-Binding Proteins ,030220 oncology & carcinogenesis ,Transcription ,Animals ,Antigens ,Nuclear ,Apoptotic Protease-Activating Factor 1 ,Cell Line ,Gene Expression Regulation ,Humans ,Hydrogen Peroxide ,Promoter Regions ,Genetic ,Protein Binding ,Repressor Proteins ,Spectrometry ,Mass ,Matrix-Assisted Laser Desorption-Ionization ,DNA Damage ,Human ,Settore BIO/06 ,DNA repair ,DNA damage ,DNA-Binding Protein ,Repressor ,Biology ,03 medical and health sciences ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,DNA repair complex ,APAF1 ,Molecular Biology ,Ku Autoantigen ,030304 developmental biology ,Original Paper ,Animal ,apoptosome ,Cell Biology ,Repressor Protein ,Molecular biology ,Apoptosome - Abstract
International audience; Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, since it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and down-regulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a down-regulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 up-regulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival
- Published
- 2011
49. Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases.
- Author
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Di Rienzo M, Romagnoli A, Refolo G, Vescovo T, Ciccosanti F, Zuchegna C, Lozzi F, Occhigrossi L, Piacentini M, and Fimia GM
- Abstract
Aging is a gradual and irreversible physiological process that significantly increases the risks of developing a variety of pathologies, including neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system diseases. Mitochondria are the energy-producing organelles, and their proper functioning is crucial for overall cellular health. Over time, mitochondrial function declines causing an increased release of harmful reactive oxygen species (ROS) and DNA, which leads to oxidative stress, inflammation and cellular damage, common features associated with various age-related pathologies. The impairment of mitophagy, the selective removal of damaged or dysfunctional mitochondria by autophagy, is relevant to the development and progression of age-related diseases. The molecular mechanisms that regulates mitophagy levels in aging remain largely uncharacterized. AMBRA1 is an intrinsically disordered scaffold protein with a unique property of regulating the activity of both proliferation and autophagy core machineries. While the role of AMBRA1 during embryonic development and neoplastic transformation has been extensively investigated, its functions in post-mitotic cells of adult tissues have been limited due to the embryonic lethality caused by AMBRA1 deficiency. Recently, a key role of AMBRA1 in selectively regulating mitophagy in post-mitotic cells has emerged. Here we summarize and discuss these results with the aim of providing a comprehensive view of the mitochondrial roles of AMBRA1, and how defective activity of AMBRA1 has been functionally linked to mitophagy alterations observed in age-related degenerative disorders, including muscular dystrophy/sarcopenia, Parkinson diseases, Alzheimer diseases and age-related macular degeneration. Abbreviations: AD: Alzheimer disease; AMD: age-related macular degeneration; AMBRA1: autophagy and beclin 1 regulator 1; APOE4: apolipoprotein E4; ATAD3A: ATPase family AAA domain containing 3A; ATG: autophagy related; BCL2: BCL2 apoptosis regulator; BH3: BCL2-homology-3; BNIP3L/NIX: BCL2 interacting protein 3 like; CDK: cyclin dependent kinase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CRL2: CUL2-RING ubiquitin ligase; DDB1: damage specific DNA binding protein 1; ER: endoplasmic reticulum; FOXO: forkhead box O; FUNDC1: FUN14 domain containing 1; GBA/β-glucocerebrosidase: glucosylceramidase beta; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IDR: intrinsically disordered region; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; MCL1: MCL1 apoptosis regulator, BCL2 family member; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MSA: multiple system atrophy; MYC: MYC proto-oncogene, bHLH transcription factor; NUMA1: nuclear mitotic apparatus protein 1; OMM; mitochondria outer membrane; PD: Parkinson disease; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PTK2/FAK: protein tyrosine kinase 2; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SAD: sporadic AD; SOCS3: suppressor of cytokine signaling 3; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; STING1: stimulator of interferon response cGAMP interactor 1; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TGFB/TGFβ: transforming growth factor beta; TOMM: translocase of outer mitochondrial membrane; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; ULK1: unc-51 like autophagy activating kinase 1.
- Published
- 2024
- Full Text
- View/download PDF
50. A microRNA Arising from the Negative Strand of SARS-CoV-2 Genome Targets FOS to Reduce AP-1 Activity.
- Author
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Greco F, Lorefice E, Carissimi C, Laudadio I, Ciccosanti F, Di Rienzo M, Colavita F, Meschi S, Maggi F, Fimia GM, and Fulci V
- Abstract
Virus-encoded microRNAs were first reported in the Epstein-Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to the herpesviridae family. To date, only 30 viral miRNAs encoded by RNA viruses are reported by miRBase. Since the outbreak of the SARS-CoV-2 pandemic, several studies have predicted and, in some cases, experimentally validated miRNAs originating from the positive strand of the SARS-CoV-2 genome. By integrating NGS data analysis and qRT-PCR approaches, we found that SARS-CoV-2 also encodes for a viral miRNA arising from the minus (antisense) strand of the viral genome, in the region encoding for ORF1ab, herein referred to as SARS-CoV-2-miR-AS1. Our data show that the expression of this microRNA increases in a time course analysis of SARS-CoV-2 infected cells. Furthermore, enoxacin treatment enhances the accumulation of the mature SARS-CoV-2-miR-AS1 in SARS-CoV-2 infected cells, arguing for a Dicer-dependent processing of this small RNA. In silico analysis suggests that SARS-CoV-2-miR-AS1 targets a set of genes which are translationally repressed during SARS-CoV-2 infection. We experimentally validated that SARS-CoV-2-miR-AS1 targets FOS, thus repressing the AP-1 transcription factor activity in human cells.
- Published
- 2023
- Full Text
- View/download PDF
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