16 results on '"Artuso, Simona"'
Search Results
2. Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model
- Author
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Alessandri, Giulio, Leonetti, Carlo, Artuso, Simona, Benetti, Anna, Dessy, Enrico, Pascucci, Luisa, Passeri, Daniela, Orlandi, Augusto, Berenzi, Angiola, Bonomi, Arianna, Coccè, Valentina, Ceserani, Valentina, Portolani, Nazario, Ceccarelli, Piero, and Pessina, Augusto
- Published
- 2015
3. Adipose-derived stem cell-mediated paclitaxel delivery inhibits breast cancer growth.
- Author
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Scioli, Maria Giovanna, Artuso, Simona, D'Angelo, Carmen, Porru, Manuela, D’Amico, Federico, Bielli, Alessandra, Gentile, Pietro, Cervelli, Valerio, Leonetti, Carlo, and Orlandi, Augusto
- Subjects
- *
BREAST cancer , *PACLITAXEL , *MAMMAPLASTY , *CANCER cell growth , *CANCER cell proliferation , *PREVENTION - Abstract
Breast cancer represents the main malignancy in women and autologous fat grafting is a diffuse procedure in the management of post-surgical breast defects causing patients’ psychosocial problems, with high costs for the public health. Recently, beneficial effects of fat grafting during post-surgical breast reconstruction have been amplified from the enrichment with human adipose-derived stem cells (ASCs) present in the stromal vascular fraction (SVF) of adult adipose tissue isolated during intraoperatory procedures. The major concern about the ASC enrichment during post-surgery breast reconstruction depends on their potential ability to release growth factors and hormones that can promote proliferation of residual or quiescent cancer cells, with the risk of de novo cancer development or recurrence. The recent description that adult stem cells primed in vitro may be vehicle for anti-cancer drug delivery offers a new vision concerning the role of ASCs in breast reconstruction after cancer surgery. Paclitaxel (PTX) is a chemotherapeutic agent acting as a microtubule-stabilizing drug inhibiting cancer cell mitotic activity. We optimized PTX loading and release in cultured ASCs and then analyzed the effects of PTX-loaded ASCs and their conditioned medium on CG5 breast cancer survival, proliferation and apoptosis in vitro, and inCG5 xenograft in vivo. We documented that ASCs can uptake and release PTX in vitro, with slight cytotoxic effects. Interestingly, PTX-loaded ASCs in co-culture, as well as conditioned medium alone, inhibited CG5 cell proliferation and survival in vitro and xenograft tumor growth in vivo. The antitumor effect of PTX-loaded ASCs may offer a new perspective concerning the use of ASCs during breast reconstruction becoming an additional local preventive chemotherapeutic agent against tumor recurrence. However, further experiments in vitro and in vivo are needed to collect more evidence confirming the efficacy and safety in cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
4. Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance.
- Author
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Zizza, Pasquale, Cingolani, Chiara, Artuso, Simona, Salvati, Erica, Rizzo, Angela, D'Angelo, Carmen, Porru, Manuela, Pagano, Bruno, Amato, Jussara, Randazzo, Antonio, Novellino, Ettore, Stoppacciaro, Antonella, Gilson, Eric, Stassi, Giorgio, Leonetti, Carlo, and Biroccio, Annamaria
- Published
- 2016
- Full Text
- View/download PDF
5. Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model.
- Author
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Pessina, Augusto, Leonetti, Carlo, Artuso, Simona, Benetti, Anna, Dessy, Enrico, Pascucci, Luisa, Passeri, Daniela, Orlandi, Augusto, Berenzi, Angiola, Bonomi, Arianna, Coccè, Valentina, Ceserani, Valentina, Ferri, Anna, Dossena, Marta, Mazzuca, Pietro, Ciusani, Emilio, Ceccarelli, Piero, Caruso, Arnaldo, Portolani, Nazario, and Sisto, Francesca
- Subjects
MESENCHYMAL stem cells ,METASTASIS ,LUNG cancer ,ANTINEOPLASTIC agents ,CANCER cell growth ,LABORATORY mice - Abstract
Background: Mesenchymal stromal cells (MSCs) are considered an important therapeutic tool in cancer therapy. They possess intrinsic therapeutic potential and can also be in vitro manipulated and engineered to produce therapeutic molecules that can be delivered to the site of diseases, through their capacity to home pathological tissues. We have recently demonstrated that MSCs, upon in vitro priming with anti-cancer drug, become drug-releasing mesenchymal cells (Dr-MCs) able to strongly inhibit cancer cells growth. Methods: Murine mesenchymal stromal cells were loaded with Paclitaxel (Dr-MCsPTX) according to a standardized procedure and their ability to inhibit the growth of a murine B16 melanoma was verified by in vitro assays. The anti-metastatic activity of Dr-MCsPTX was then studied in mice injected i.v. with B16 melanoma cells that produced lung metastatic nodules. Lung nodules were counted under a dissecting stereomicroscope and metastasis investigated by histological analysis. Results: We found that three i.v. injections of Dr-MCsPTX on day 5, 10 and 15 after tumor injection almost completely abolished B16 lung metastasis. Dr-MCsPTX arrested into lung by interacting with endothelium and migrate toward cancer nodule through a complex mechanism involving primarily mouse lung stromal cells (mL-StCs) and SDF-1/ CXCR4/CXCR7 axis. Conclusions: Our results show for the first time that Dr-MCsPTX are very effective to inhibit lung metastasis formation. Actually, a cure for lung metastasis in humans is mostly unlikely and we do not know whether a therapy combining engineered MSCs and Dr-MCs may work synergistically. However, we think that our approach using Dr-MCs loaded with PTX may represent a new valid and additive therapeutic tool to fight lung metastases and, perhaps, primary lung cancers in human. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
6. Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities.
- Author
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Rizzo, Angela, Iachettini, Sara, Zizza, Pasquale, Cingolani, Chiara, Porru, Manuela, Artuso, Simona, Stevens, Malcolm, Hummersone, Marc, Biroccio, Annamaria, Salvati, Erica, and Leonetti, Carlo
- Subjects
LIGANDS (Biochemistry) ,TOXICOLOGY ,TELOMERES ,CANCER treatment ,PENTACYCLOUNDECANES - Abstract
The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant β2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off-target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
7. The microRNA miR-92 increases proliferation of myeloid cells and by targeting p63 modulates the abundance of its isoforms.
- Author
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Manni, Isabella, Artuso, Simona, Careccia, Silvia, Rizzo, Maria Giulia, Baserga, Renato, Piaggio, Giulia, and Sacchi, Ada
- Subjects
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RNA , *PROTEINS , *APOPTOSIS , *CELL proliferation , *OLIGONUCLEOTIDES - Abstract
MicroRNAs (miRs) are 21- to 23-nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs of proteins involved in cell growth and apoptosis, miR-92 is part of the mir-17-92 cluster, which comprises members with an effect on cell proliferation. However, the role of miR-92 is unknown, and its targets have not been identified. Here, we describe a mechanism through which miR-92 contributes to regulate cell proliferation. Using a miR-92 synthetic double-strand oligonucleotide, we demonstrate that miR-92 increases 32D myeloid cell proliferation and 5-bromo-2-deoxyuridine (BrdU) incorporation and inhibits cell death. The effect is miR-92 specific since the miR-92 antagomir inhibits cell proliferation. Moreover, we show that miR-92 acts by modulating p63-isoform abundance through down-regulatation of endogenous ΔNp63β. Using luciferase reporters containing p63 3′UTR fragments with wild-type or mutant miR-92 complementary sites, we demonstrate that the wild-type 3′UTR is a direct target of miR-92. Finally, we observed that a miR-92-resistant ΔNp63β isoform (without 3′UTR) inhibits cell proliferation and parallels the effect of the antagomir. We conclude that one of the molecular mechanisms through which miR-92 increases cell proliferation is by negative regulation of an isoform of the cell-cycle regulator p63. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
8. A Nitric Oxide-dependent Cross-talk between Class I and III Histone Deacetylases Accelerates Skin Repair.
- Author
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Spallotta, Francesco, Cencioni, Chiara, Stefania Straino, Nanni, Simona, Rosati, Jessica, Artuso, Simona, Manni, Isabella, Colussi, Claudia, Piaggio, Giulia, Martelli, Fabio, Valente, Sergio, Mai, Antonello, Capogrossi, Maurizio C., Farsetti, Antonella, and Gaetano, Carlo
- Subjects
- *
NITRIC oxide , *HISTONE deacetylase , *WOUND healing , *KERATINOCYTES , *CELL proliferation , *SKIN regeneration - Abstract
In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF- 10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
9. Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid
- Author
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Sara Lusa, Simona Artuso, Amalia Luce, Giuseppe De Rosa, Antonella Stoppacciaro, Michele Caraglia, Manuela Porru, Maria Luisa Balestrieri, Silvia Zappavigna, Carlo Leonetti, Giuseppina Salzano, Porru, Manuela, Zappavigna, Silvia, Salzano, Giuseppina, Luce, Amalia, Stoppacciaro, Antonella, Balestrieri, MARIA LUISA, Artuso, Simona, Lusa, Sara, DE ROSA, Giuseppe, Leonetti, Carlo, Caraglia, Michele, Porru, M, Zappavigna, S, Salzano, G, Luce, A, Stoppacciaro, A, Balestrieri, Maria Luisa, Artuso, S, Lusa, S, De Rosa, G, and Leonetti, C
- Subjects
Male ,intracranial xenografts ,Apoptosis ,Pharmacology ,Zoledronic Acid ,Mice, Inbred Strain ,Nitrosourea Compounds ,Mice ,Drug Delivery Systems ,Nanoparticle ,Neoplasm ,chemistry.chemical_classification ,Cell Growth Processe ,Diphosphonates ,calcium phosphate self-assembly nanoparticles ,Brain Neoplasms ,Imidazoles ,Transferrin ,Tumor Burden ,Dacarbazine ,medicine.anatomical_structure ,Diphosphonate ,Oncology ,Blood-Brain Barrier ,Drug delivery ,delivery ,Research Paper ,Human ,medicine.drug ,Glioblastoma ,zoledronic acid ,transferrin ,Mice, Inbred Strains ,Cell Growth Processes ,Nitrosourea Compound ,Blood–brain barrier ,Brain Neoplasm ,Organophosphorus Compounds ,Cell Line, Tumor ,Temozolomide ,medicine ,Animals ,Humans ,Imidazole ,Animal ,business.industry ,technology, industry, and agriculture ,Apoptosi ,medicine.disease ,Xenograft Model Antitumor Assays ,Zoledronic acid ,chemistry ,Drug Resistance, Neoplasm ,Nanoparticles ,Fotemustine ,Organophosphorus Compound ,business ,Drug Delivery System - Abstract
Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB.
- Published
- 2014
10. Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2.
- Author
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Gnani D, Romito I, Artuso S, Chierici M, De Stefanis C, Panera N, Crudele A, Ceccarelli S, Carcarino E, D'Oria V, Porru M, Giorda E, Ferrari K, Miele L, Villa E, Balsano C, Pasini D, Furlanello C, Locatelli F, Nobili V, Rota R, Leonetti C, and Alisi A
- Subjects
- Aminopyridines pharmacology, Animals, Apoptosis drug effects, Apoptosis genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation drug effects, E2F2 Transcription Factor genetics, E2F2 Transcription Factor metabolism, E2F3 Transcription Factor genetics, E2F3 Transcription Factor metabolism, Enhancer of Zeste Homolog 2 Protein metabolism, Focal Adhesion Kinase 1 antagonists & inhibitors, Focal Adhesion Kinase 1 metabolism, G2 Phase Cell Cycle Checkpoints, Hep G2 Cells, Histones genetics, Histones metabolism, Humans, Liver Neoplasms metabolism, Liver Neoplasms pathology, Male, Mice, Mice, Nude, Neoplasm Transplantation, Promoter Regions, Genetic, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Receptor, Notch2 metabolism, Signal Transduction, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Carcinoma, Hepatocellular genetics, Enhancer of Zeste Homolog 2 Protein genetics, Focal Adhesion Kinase 1 genetics, Gene Expression Regulation, Neoplastic, Liver Neoplasms genetics, Receptor, Notch2 genetics
- Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.
- Published
- 2017
- Full Text
- View/download PDF
11. Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer.
- Author
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Porru M, Artuso S, Salvati E, Bianco A, Franceschin M, Diodoro MG, Passeri D, Orlandi A, Savorani F, D'Incalci M, Biroccio A, and Leonetti C
- Subjects
- Animals, Cell Line, Tumor, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Humans, Male, Metabolomics methods, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Microscopy, Fluorescence, Treatment Outcome, Tumor Burden drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, G-Quadruplexes drug effects, Imides pharmacology, Nucleic Acid Conformation drug effects, Piperidines pharmacology
- Abstract
We previously identified EMICORON as a novel G-quadruplex (G4) ligand showing high selectivity for G4 structures over the duplex DNA, causing telomere damage and inhibition of cell proliferation in transformed and tumor cells. Here, we evaluated the antitumoral effect of EMICORON on advanced models of human colon cancer that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDX) and orthotopic colon cancer and strongly reduced the dissemination of tumor cells to lymph nodes, intestine, stomach, and liver. Finally, activation of DNA damage and impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human colon cancer that bridge the translational gap between preclinical and clinical studies, demonstrated that EMICORON had an unprecedented antitumor activity warranting further studies of EMICORON-based combination treatments., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
12. Erratum: identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities.
- Author
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Rizzo A, Iachettini S, Zizza P, Cingolani C, Porru M, Artuso S, Stevens M, Hummersone M, Biroccio A, Salvati E, and Leonetti C
- Published
- 2015
- Full Text
- View/download PDF
13. Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid.
- Author
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Porru M, Zappavigna S, Salzano G, Luce A, Stoppacciaro A, Balestrieri ML, Artuso S, Lusa S, De Rosa G, Leonetti C, and Caraglia M
- Subjects
- Animals, Apoptosis drug effects, Blood-Brain Barrier drug effects, Cell Growth Processes drug effects, Cell Line, Tumor, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Diphosphonates chemistry, Drug Resistance, Neoplasm, Glioblastoma immunology, Humans, Imidazoles chemistry, Male, Mice, Mice, Inbred Strains, Nanoparticles chemistry, Nitrosourea Compounds therapeutic use, Organophosphorus Compounds therapeutic use, Temozolomide, Transferrin chemistry, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Zoledronic Acid, Brain Neoplasms drug therapy, Diphosphonates administration & dosage, Drug Delivery Systems methods, Glioblastoma drug therapy, Imidazoles administration & dosage, Nanoparticles administration & dosage
- Abstract
Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB.
- Published
- 2014
- Full Text
- View/download PDF
14. Molecular imaging of nuclear factor-Y transcriptional activity maps proliferation sites in live animals.
- Author
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Goeman F, Manni I, Artuso S, Ramachandran B, Toietta G, Bossi G, Rando G, Cencioni C, Germoni S, Straino S, Capogrossi MC, Bacchetti S, Maggi A, Sacchi A, Ciana P, and Piaggio G
- Subjects
- Animals, Cell Cycle genetics, Cell Line, Cyclin B2 genetics, DNA-Binding Proteins genetics, Genes, Reporter, Luciferases genetics, Luciferases metabolism, Mice, Mice, Transgenic, Promoter Regions, Genetic, CCAAT-Binding Factor genetics, CCAAT-Binding Factor metabolism, Cell Proliferation, Liver Regeneration, Molecular Imaging, Transcription, Genetic
- Abstract
In vivo imaging involving the use of genetically engineered animals is an innovative powerful tool for the noninvasive assessment of the molecular and cellular events that are often targets of therapy. On the basis of the knowledge that the activity of the nuclear factor-Y (NF-Y) transcription factor is restricted in vitro to proliferating cells, we have generated a transgenic reporter mouse, called MITO-Luc (for mitosis-luciferase), in which an NF-Y-dependent promoter controls luciferase expression. In these mice, bioluminescence imaging of NF-Y activity visualizes areas of physiological cell proliferation and regeneration during response to injury. Using this tool, we highlight for the first time a role of NF-Y activity on hepatocyte proliferation during liver regeneration. MITO-Luc reporter mice should facilitate investigations into the involvement of genes in cell proliferation and provide a useful model for studying aberrant proliferation in disease pathogenesis. They should be also useful in the development of new anti/proproliferative drugs and assessment of their efficacy and side effects on nontarget tissues.
- Published
- 2012
- Full Text
- View/download PDF
15. Transcription factor NF-Y induces apoptosis in cells expressing wild-type p53 through E2F1 upregulation and p53 activation.
- Author
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Gurtner A, Fuschi P, Martelli F, Manni I, Artuso S, Simonte G, Ambrosino V, Antonini A, Folgiero V, Falcioni R, Sacchi A, and Piaggio G
- Subjects
- Animals, Blotting, Western, CCAAT-Binding Factor genetics, CCAAT-Binding Factor metabolism, Cell Line, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, E2F1 Transcription Factor genetics, Embryo, Mammalian cytology, Fibroblasts cytology, Fibroblasts metabolism, HCT116 Cells, HeLa Cells, Humans, Mice, Mice, Knockout, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction physiology, Tumor Suppressor Protein p53 genetics, Apoptosis physiology, CCAAT-Binding Factor physiology, E2F1 Transcription Factor metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
The CCAAT-binding transcription factor NF-Y plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell-cycle progression such as cyclin A, cyclin B1, cyclin B2, cdc25A, cdc25C, and cdk1. Here we show that unrestricted NF-Y activity leads to apoptosis in an E2F1- and wild-type p53 (wtp53)-dependent manner. Unrestricted NF-Y activity induced an increase in E2F1 mRNA and protein levels. Furthermore, NF-Y directly bound the E2F1 promoter and this correlated with the appearance of open chromatin marks. The ability of NF-Y to induce apoptosis was impaired in cells lacking E2F1 and wtp53. Moreover, NF-Y overexpression elicited phosphorylation of wt p53Ser18 in an E2F1-dependent manner. Our findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis.
- Published
- 2010
- Full Text
- View/download PDF
16. Posttranslational regulation of NF-YA modulates NF-Y transcriptional activity.
- Author
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Manni I, Caretti G, Artuso S, Gurtner A, Emiliozzi V, Sacchi A, Mantovani R, and Piaggio G
- Subjects
- Amino Acid Sequence, Animals, CCAAT-Binding Factor genetics, Cell Line, Humans, Lysine genetics, Lysine metabolism, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors, Protein Subunits genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Alignment, Ubiquitination, p300-CBP Transcription Factors metabolism, CCAAT-Binding Factor metabolism, Gene Expression Regulation, Protein Processing, Post-Translational, Protein Subunits metabolism, Transcription, Genetic
- Abstract
NF-Y binds to CCAAT motifs in the promoter region of a variety of genes involved in cell cycle progression. The NF-Y complex comprises three subunits, NF-YA, -YB, and -YC, all required for DNA binding. Expression of NF-YA fluctuates during the cell cycle and is down-regulated in postmitotic cells, indicating its role as the regulatory subunit of the complex. Control of NF-YA accumulation is posttranscriptional, NF-YA mRNA being relatively constant. Here we show that the levels of NF-YA protein are regulated posttranslationally by ubiquitylation and acetylation. A NF-YA protein carrying four mutated lysines in the C-terminal domain is more stable than the wild-type form, indicating that these lysines are ubiquitylated Two of the lysines are acetylated in vitro by p300, suggesting a competition between ubiquitylation and acetylation of overlapping residues. Interestingly, overexpression of a degradation-resistant NF-YA protein leads to sustained expression of mitotic cyclin complexes and increased cell proliferation, indicating that a tight regulation of NF-YA levels contributes to regulate NF-Y activity.
- Published
- 2008
- Full Text
- View/download PDF
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