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Search Results: 1 - 10 of 18545 matches for " Alberto Gulino "
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Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells
Veronica Veschi, Marialaura Petroni, Beatrice Cardinali, Carlo Dominici, Isabella Screpanti, Luigi Frati, Armando Bartolazzi, Alberto Gulino, Giuseppe Giannini
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049139
Abstract: MYCN amplification occurs in about 20–25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.
The TrkAIII Oncoprotein Inhibits Mitochondrial Free Radical ROS-Induced Death of SH-SY5Y Neuroblastoma Cells by Augmenting SOD2 Expression and Activity at the Mitochondria, within the Context of a Tumour Stem Cell-like Phenotype
Pierdomenico Ruggeri, Antonietta R. Farina, Natalia Di Ianni, Lucia Cappabianca, Marzia Ragone, Giulia Ianni, Alberto Gulino, Andrew R. Mackay
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094568
Abstract: The developmental and stress-regulated alternative TrkAIII splice variant of the NGF receptor TrkA is expressed by advanced stage human neuroblastomas (NBs), correlates with worse outcome in high TrkA expressing unfavourable tumours and exhibits oncogenic activity in NB models. In the present study, we report that constitutive TrkAIII expression in human SH-SY5Y NB cells inhibits Rotenone, Paraquat and LY83583-induced mitochondrial free radical reactive oxygen species (ROS)-mediated death by stimulating SOD2 expression, increasing mitochondrial SOD2 activity and attenuating mitochondrial free radical ROS production, in association with increased mitochondrial capacity to produce H2O2, within the context of a more tumour stem cell-like phenotype. This effect can be reversed by the specific TrkA tyrosine kinase inhibitor GW441756, by the multi-kinase TrkA inhibitors K252a, CEP-701 and G?6976, which inhibit SOD2 expression, and by siRNA knockdown of SOD2 expression, which restores the sensitivity of TrkAIII expressing SH-SY5Y cells to Rotenone, Paraquat and LY83583-induced mitochondrial free radical ROS production and ROS-mediated death. The data implicate the novel TrkAIII/SOD2 axis in promoting NB resistance to mitochondrial free radical-mediated death and staminality, and suggest that the combined use of TrkAIII and/or SOD2 inhibitors together with agents that induce mitochondrial free radical ROS-mediated death could provide a therapeutic advantage that may also target the stem cell niche in high TrkA expressing unfavourable NB.
Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma
Antonella Calogero, Vincenza Lombari, Giorgia De Gregorio, Antonio Porcellini, Severine Ucci, Antonietta Arcella, Riccardo Caruso, Franco Gagliardi, Alberto Gulino, Gaetano Lanzetta, Luigi Frati, Dan Mercola, Giuseppe Ragona
Cancer Cell International , 2004, DOI: 10.1186/1475-2867-4-1
Abstract: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1–2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus.Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.EGR-1 encodes a nuclear phosphoprotein that binds to DNA and regulates transcription through a GC-rich consensus sequence [1-4]. EGR-1 is involved in the regulation of cell responses to a wide array of stimuli such as mitogens, growth factors and stress stimuli [5-7]. Recent studies have shown that EGR-1 expression is altered in several types of neoplasia, compared to normal tissue [1,8,9]. Gene deletion or EGR-1 mutations have been reported in sporadic hematological malignancies [10]. EGR-1 expression has been found to be either decreased or undetectable in human breast cancer tissue and small cell lung carcinoma [11,12]. EGR-1 is altered in a different manner in prostate cancer, where higher levels of EGR-1 expression are found correlated to more advanced stages of malignancy [13]. Later studies confirmed in two independent mouse models that EGR-1 up-regulates tumor progression [14,15]. From these various studies it is clear that EGR-1 is involved in regulation of
Recovery of NIS expression in thyroid cancer cells by overexpression of Pax8 gene
Ivan Presta, Franco Arturi, Elisabetta Ferretti, Tiziana Mattei, Daniela Scarpelli, Emanuele Tosi, Angela Scipioni, Marilena Celano, Alberto Gulino, Sebastiano Filetti, Diego Russo
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-80
Abstract: In this study, the anaplastic thyroid carcinoma ARO cells were stably transfected with a Pax8 gene expression vector. A quantitative RT-PCR was performed to assess the thyroid specific gene expression in selected clones. The presence of NIS protein was detected by Western blot and localized by immunofluorescence. A iodide uptake assay was also performed to verify the functional effect of NIS induction and differentiation switch.The clones overexpressing Pax8 showed the re-activation of several thyroid specific genes including NIS, Pendrin, Thyroglobulin, TPO and TTF1. In ARO-Pax8 clones NIS protein was also localized both in cell cytoplasm and membrane. Thus, the ability to uptake the radioiodine was partially restored, associated to a high rate of efflux. In addition, ARO cells expressing Pax8 presented a lower rate of cell growth.These finding demonstrate that induction of Pax8 expression may determine a re-differentiation of thyroid cancer cells, including a partial recovery of iodide uptake, fundamental requisite for a radioiodine-based therapeutic approach for thyroid tumours.Thyroid tumours show a good long-term survival, but, when we consider the poorly differentiated histotypes and in particular the anaplastic carcinoma, the prognosis is very poor [1,2]. A major determinant of such an opposite behaviour is the lost ability to concentrate the radioiodine, used as very effective tool for diagnosis and treatment for both tumour remnants or distant metastases [3]. The loss of iodide uptake capacity in poorly differentiated thyroid carcinomas is mainly due to the reduced/lost functional expression of the sodium/iodide symporter (NIS), with a defect occurring mainly at gene expression level, but in some case involving post-transcriptional or other unknown alterations [4-7]. For this reason, many strategies have been used and are currently in progress in order to re-establish iodide uptake function by means of re-expressing the NIS in tumour cells. At present, two
The tumor suppressor gene KCTD11REN is regulated by Sp1 and methylation and its expression is reduced in tumors
M Michela Mancarelli, Francesca Zazzeroni, Lucia Ciccocioppo, Daria Capece, Agnese Po, Simona Murgo, Raffaello Di Camillo, Christian Rinaldi, Elisabetta Ferretti, Alberto Gulino, Edoardo Alesse
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-172
Abstract: TSGs often locate at chromosomal regions, which are frequently deleted and/or methylated in tumors. High levels of 17p13 somatic alterations have been showed in several tumors, distal and independent of the p53 locus [1-4].Our group has identified KCTD11 as an immediate-early gene induced by neurogenic signals [5] and encoding a novel adaptor of Cullin3 ubiquitin E3 ligase complex targeting Histone Deacetylase 1 [6]. Importantly, KCTD11 is a novel TSG that inhibits cell growth and is mapping on human chromosome 17p13.2, whose expression is frequently lost in human MB [4].To analyze whether the down-regulation of KCTD11 represents a specific feature of MB, as well to other cancers, we performed a wide screening for KCTD11 expression, analyzing 177 human tumor samples and 177 normal matching samples, representing 18 different cancer types. Normal tissues, including larynx, esophagus, stomach, colon-rectum, urinary bladder, lung, breast, gallbladder and endometrium, exhibited a nuclear KCTD11 positive immunohistochemical staining between 40 to 78% (Fig. 1B), whereas the matching tumor samples showed a significant reduction of 0 to 18% of nuclear KCTD11 staining (Fig. 1A and 1B). Reduced KCTD11 expression was not observed in thyroid and kidney tumor tissues vs normal suggesting a tumorigenic specific role of KCTD11 for the above mentioned tissues (Fig. 1A and 1B and data not shown). Moreover KCTD11 was undetected both in normal and cancer tissues from liver, lymph-node and exocrine pancreas (data not shown). Together, these findings clearly indicated that selective tissues expressing KCTD11 have down-regulated this gene during tumorigenesis.To understand the transcriptional regulation of KCTD11, we identified and analyzed the promoter region. Human KCTD11 proximal promoter is a 623 bp region (Fig. 2A). It turned out to be a TATA- and CAAT-less promoter. The transcription start site (TSS) was previously identified [4] (Fig. 2A). Using the TRANSFACT software, we identifie
A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders
Daria Capece, Francesca Zazzeroni, Maria Michela Mancarelli, Daniela Verzella, Mariafausta Fischietti, Ambra Di Tommaso, Rita Maccarone, Sara Plebani, Mauro Di Ianni, Alberto Gulino, Edoardo Alesse
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068080
Abstract: The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders.
Gli2 Acetylation at Lysine 757 Regulates Hedgehog-Dependent Transcriptional Output by Preventing Its Promoter Occupancy
Sonia Coni, Laura Antonucci, Davide D'Amico, Laura Di Magno, Paola Infante, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Isabella Screpanti, Alberto Gulino, Gianluca Canettieri
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065718
Abstract: The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p300, but not other HATs, acetylates Gli2 at the conserved lysine K757 thus inhibiting Hh target gene expression. By generating a specific anti acetyl-Gli2(Lys757) antisera we demonstrated that Gli2 acetylation is readily detectable at endogenous levels and is attenuated by Hh agonists. Moreover, Gli2 K757R mutant activity is higher than wild type Gli2 and is no longer enhanced by Hh agonists, indicating that acetylation represents an additional level of control for signal dependent activation. Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling. Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin. Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.
Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma
Cucchi D, Occhione MA, Gulino A, De Smaele E
Journal of Experimental Pharmacology , 2012, DOI: http://dx.doi.org/10.2147/JEP.S28553
Abstract: gehog signaling pathway and its targets for treatment in basal cell carcinoma Review (776) Total Article Views Authors: Cucchi D, Occhione MA, Gulino A, De Smaele E Published Date December 2012 Volume 2012:4 Pages 173 - 185 DOI: http://dx.doi.org/10.2147/JEP.S28553 Received: 06 September 2012 Accepted: 02 November 2012 Published: 17 December 2012 Danilo Cucchi,1,* Maria Anna Occhione,2,* Alberto Gulino,2,3 Enrico De Smaele1 1Department of Experimental Medicine, 2Department of Molecular Medicine, Sapienza University of Rome, Rome, 3Center of Life NanoScience @ La Sapienza, Istituto Italiano di Tecnologia, Rome, Italy *These authors contributed equally to this work Abstract: Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified – from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib – most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.
The Old Roots of the Italian Health Legislation
Caterina Bassetti,Matteo Gulino,Valentina Gazzaniga,Paola Frati
Mediterranean Journal of Social Sciences , 2011,
Abstract: urrent Italian Health legislation is a paradigmatic example of a system based on the fundamental principles of the safeguard and right to individual health.This raises the question of its evolution and gradual shaping stemming from very old and deep roots. Such a long process started in the second half of the 19th century, when the newly reunified Kingdom of Italy, born in 1861, started to face the issue of a very obsolete health system. A number of laws sequentially provided the regulation of physician activities and health care for all people in need, regardless of their economic status and without any religious or political belief distinction, and culminate in the “Comprehensive Law on Health” enacted in 1934. These whole systems of laws have oriented the legislation on health care and organization, becoming a fundamental landmark until the promulgation of the Italian Constitution in 1948.
HEPATITIS B AND C IN HEMATOPOIETIC STEM CELL TRANSPLANT
Anna Locasciulli,Barbara Montante,Emanuela Morelli,Virginia Gulino
Mediterranean Journal of Hematology and Infectious Diseases , 2009, DOI: 10.4084/mjhid.2011.
Abstract: Although the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT > 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.
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