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3. Structural characterization of PHOX2B and its DNA interaction shed light on the molecular basis of the +7Ala variant pathogenicity in CCHS.

Author

Diana, Donatella, Pirone, Luciano, Russo, Luigi, D'Abrosca, Gianluca, Madheswaran, Manoj, Benfante, Roberta, Di Lascio, Simona, Caldinelli, Laura, Fornasari, Diego, Acconcia, Clementina, Corvino, Andrea, Ventserova, Nataliia, Pollegioni, Loredano, Isernia, Carla, Di Gaetano, Sonia, Malgieri, Gaetano, Pedone, Emilia M., and Fattorusso, Roberto

Published
2024
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4. Structural characterization of PHOX2B and its DNA interaction shed lights into the molecular basis of the + 7Ala variant pathogenicity in CCHS

Author

Diana, Donatella, primary, Pirone, Luciano, additional, Russo, Luigi, additional, D'Abrosca, Gianluca, additional, Madheswaran, Manoj, additional, Benfante, Roberta, additional, Di Lascio, Simona, additional, Caldinelli, Laura, additional, Fornasari, D., additional, Acconcia, Clementina, additional, Corvino, Andrea, additional, Ventserova, Nataliia, additional, Pollegioni, Loredano, additional, Isernia, Carla, additional, Di Gaetano, Sonia, additional, Malgieri, Gaetano, additional, Pedone, Emilia, additional, and Fattorusso, Roberto, additional

Published
2024
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6. Dissection analysis of the negative regulation of the human urokinase-type plasminogen activator (uPA) gene

Author

Benfante, Roberta

Subjects
572
Abstract

The urokinase-type plasminogen activator (uPA) is a serine protease involved in processes such as cell migration and invasion through the activation of the extracellular protease plasmin responsible of the degradation of the proteins of the extracellular matrix. The ability of the cells to migrate and to invade the surrounding tissues plays a fundamental role in many normal and pathological processes such as fibrinolysis, wound healing, angiogenesis, embryogenesis, gametogenesis, ovulation, mammary gland involution and tumor metastasis. Due to its high destructive potential, localized activation of plasminogen is regulated by a complex network of molecular interactions involving both specific inhibitors (PAI-1 and PAI-2), and cell bound receptor (uPAR) and the synthesis of every component of the plasminogen activator system is tightly regulated by a number of factors like hormones, growth factors and cytokines. On the other hand, the restricted expression of uPA in the organism to a very few cell types (kidney and lung), its inducibility by different stimuli and its overexpression in tumours and several transformed and tumoral cell lines, indicate that uPA regulation occurs also at the level of gene expression. The gene encoding uPA and its 5' flanking region have been sequenced and characterized in human, mouse and pig. Both in vivo and in vitro studies of progressive 5'deletions of the regulatory region of uPA, have revealed the presence of positive and negative cis-acting sequences and of specific contributions of the proximal regulatory regions to cell-type specific expression of the gene, suggesting the presence of multiple array of cis-acting sequences specific for different transcription factors that direct uPA expression in a celltype specific manner. In the human uPA promoter the enhancer is located between -2100 and -1870 from the transcriptional start site and contains two binding sites for the transcription factor API and PE A3 which are important for both the constitutive and regulated expression of the gene. Furthermore, the cooperation between the two API sites is required for TPA inducibility and is mediated by other proteins called Upstream Enhancer Factors (UEF). A negative cis-acting element has been localized between -1870 and -1570 and contains a binding site for a multiproteic complex (NF-kB/c-rel) that mediates the inducibility by TPA in HeLa and HepG2 cell lines. Much evidence, however, indicates that the regulation of uPA is mainly negative. The studies described in this thesis have led to the identification of negative regulatory elements that may play an important role in the establishment of a silenced phenotype in a cell-type specific manner. The analysis of promoter activity in cell lines not expressing (HeLa and CVl) and expressing uPA (PC3) allowed the identification of at least three regions that play different roles in the silencing of the uPA gene in different cell lines, named SI (-1870/-1428), 82 (-787/-537) and S3 (-537/-86). Of the three only S2 shows cell-type specificity, as it is active only in cells that do not express uPA; S1 and S3, on the other hand, could act as modulators of uPA gene expression in those cells that express uPA. All of them negatively regulate the activity of the minimal promoter, suggesting that they can interfere with the formation of a competent pre-initiation complex at the start site of transcription. A dissection analysis of silencer S2 detected the presence of multiple silencing units, although the deletion of a single one does not have any effect on the activity of the promoter. Transcription from a heterologous promoter is affected only when more than one copy of a single unit is cloned in front of it, suggesting that in the context of the whole S2 region each unit acts synergistically with the others in the silencing of the gene. DNase I footprinting analysis of S2 showed that this region is extensively protected by nuclear extract from uPA producing (PC-3) and not producing (HeLa) cell lines, with few differences between them. However, the LMSA analysis of the complexes indicated that their molecular composition may be different in the two cell lines tested. In particular, in HeLa cell extract, a single strand binding activity seems to bind S2 and it may be responsible for the assembly of a negative-acting complex that would prevent the loading of a competent transcription initiation complex at the start site of transcription. Furthermore, the presence of two binding sites for proteins belonging to the HMG-box containing protein family, suggested that the assembly of a stereospecific complex is required for the activity of silencer S2, although it is not clear if their activity is required for the silencing of the gene or for the inactivation of the inhibition in those cells that express uPA as in HepG2 cell line. In these cells uPA is expressed at a very low basal level, but its expression is inducible by TPA. In this cell line S2 is not active; on the contrary its presence is required for basal expression of uPA. The presence in S2 of a sequence matching the transforming growth factor β inihibitory element (TIE), described to be important for mediating the inhibition of TPA induction by TGF-βl of the stromelysin gene, has led me to investigate the role of this element on S2 activity in HepG2 cells. Transient transfection analysis of uPA promoter deletions showed that, at least in this system, the TIE is not involved in the regulation of uPA expression. Preliminary results, shown in appendix 2, have suggested another interesting aspect of the negative regulation of uPA expression by the p53 tumor suppressor gene product, although no p53 binding to uPA promoter has been shown so far. In conclusion, the studies presented in this thesis have showed that a complex array of regulatory sequences, in addition to the enhancer and minimal promoter, appear to regulate uPA transcription, some of which are cell-type specific.

Published
1999
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10. Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene

Author

Cuadros Gamboa, Ana Lucia, primary, Benfante, Roberta, additional, Nizzardo, Monica, additional, Bachetti, Tiziana, additional, Pelucchi, Paride, additional, Melzi, Valentina, additional, Arzilli, Cinzia, additional, Peruzzi, Marta, additional, Reinbold, Rolland A., additional, Cardani, Silvia, additional, Morrone, Amelia, additional, Guerrini, Renzo, additional, Zucchi, Ileana, additional, Corti, Stefania, additional, Ceccherini, Isabella, additional, Piumelli, Raffaele, additional, Nassi, Niccolò, additional, Di Lascio, Simona, additional, and Fornasari, Diego, additional

Published
2022
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11. eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures

Author

Heise, Christopher, Taha, Elham, Murru, Luca, Ponzoni, Luisa, Cattaneo, Angela, Guarnieri, Fabrizia C., Montani, Caterina, Mossa, Adele, Vezzoli, Elena, Ippolito, Giulio, Zapata, Jonathan, Barrera, Iliana, Ryazanov, Alexey G., Cook, James, Poe, Michael, Stephen, Michael Rajesh, Kopanitsa, Maksym, Benfante, Roberta, Rusconi, Francesco, Braida, Daniela, Francolini, Maura, Proud, Christopher G., Valtorta, Flavia, Passafaro, Maria, Sala, Mariaelvina, Bachi, Angela, Verpelli, Chiara, Rosenblum, Kobi, and Sala, Carlo

Published
2017
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16. Evidence of a dual mechanism of action underlying the anti-proliferative and cytotoxic effects of ammonium-alkyloxy-stilbene-based α7- and α9-nicotinic ligands on glioblastoma cells

Author

Pucci, Susanna, primary, Bolchi, Cristiano, additional, Bavo, Francesco, additional, Pallavicini, Marco, additional, De Palma, Clara, additional, Renzi, Massimiliano, additional, Fucile, Sergio, additional, Benfante, Roberta, additional, Di Lascio, Simona, additional, Lattuada, Donatella, additional, Bessereau, Jean-Louis, additional, D’Alessandro, Manuela, additional, Risson, Valerie, additional, Zoli, Michele, additional, Clementi, Francesco, additional, and Gotti, Cecilia, additional

Published
2022
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20. Choline and nicotine increase glioblastoma cell proliferation by binding and activating α7- and α9- containing nicotinic receptors

Author

Pucci, Susanna, primary, Fasoli, Francesca, additional, Moretti, Milena, additional, Benfante, Roberta, additional, Di Lascio, Simona, additional, Viani, Paola, additional, Daga, Antonio, additional, Gordon, Thomas J., additional, McIntosh, Michael, additional, Zoli, Michele, additional, Clementi, Francesco, additional, and Gotti, Cecilia, additional

Published
2021
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27. Target Sequencing, Cell Experiments, and a Population Study Establish Endothelial Nitric Oxide Synthase (eNOS) Gene as Hypertension Susceptibility Gene

Author

Salvi, Erika, Kuznetsova, Tatiana, Thijs, Lutgarde, Lupoli, Sara, Stolarz-Skrzypek, Katarzyna, D'Avila, Francesca, Tikhonoff, Valerie, De Astis, Silvia, Barcella, Matteo, Seidlerova, Jitka, Benaglio, Paola, Malyutina, Sofia, Frau, Francesca, Velayutham, Dinesh, Benfante, Roberta, Zagato, Laura, Title, Alexandra, Braga, Daniele, Marek, Diana, Kawecka-Jaszcz, Kalina, Casiglia, Edoardo, Filipovsky, Jan, Nikitin, Yuri, Rivolta, Carlo, Manunta, Paolo, Beckmann, Jacques S., Barlassina, Cristina, Cusi, Daniele, Staessen, Jan A., Czarnecka, Danuta, Gąsowski, Jerzy, Grodzicki, Tomasz, Kloch-Badełek, Małgorzata, Olszanecka, Agnieszka, Wizner, Barbara, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Salvi, E, Kuznetsova, T, Thijs, L, Lupoli, S, STOLARZ SKRZYPEK, K, D'Avila, F, Tikhonoff, V, DE ASTIS, S, Barcella, M, Seidlerová, J, Benaglio, P, Malyutina, S, Frau, F, Velayutham, D, Benfante, R, Zagato, L, Title, A, Braga, D, Marek, D, KAWECKA JASZCZ, K, Casiglia, E, Filipovsky, J, Nikitin, Y, Rivolta, C, Manunta, Paolo, Beckmann, J, Barlassina, C, Cusi, D, and Staessen, J. A.

Subjects
Adult, Male, medicine.medical_specialty, hypertension, Genotype, Nitric Oxide Synthase Type III, Endothelium, Population, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, target sequencing, population science, Enos, Internal medicine, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, endothelial nitric oxide synthase gene, Allele, Promoter Regions, Genetic, education, Alleles, 030304 developmental biology, 0303 health sciences, education.field_of_study, blood pressure, Promoter, Middle Aged, biology.organism_classification, Molecular biology, Endocrinology, medicine.anatomical_structure, Blood pressure, transfection, Case-Control Studies, Population study, Female, Endothelium, Vascular
Abstract

A case–control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase ( eNOS ) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% ( P TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers ( P ≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6–11.1; P =0.028) and 4.8 mm Hg diastolic (CI, 1.5–8.2; P =0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes ( P ≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24–3.37; P =0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension.

Published
2013

31. α9- and α7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line

Author

Mucchietto, Vanessa, primary, Fasoli, Francesca, additional, Pucci, Susanna, additional, Moretti, Milena, additional, Benfante, Roberta, additional, Maroli, Annalisa, additional, Di Lascio, Simona, additional, Bolchi, Cristiano, additional, Pallavicini, Marco, additional, Dowell, Cheryl, additional, McIntosh, Michael, additional, Clementi, Francesco, additional, and Gotti, Cecilia, additional

Published
2017
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33. Calciphylaxis in chronic kidney disease

Author

Li Cavoli, Gioacchino, Bono, Luisa, Tortorici, Calogera, Manno, Audenzia, Benfante, Roberta, Li Cavoli, Tancredi Vincenzo, Rotolo, Ugo, Li Cavoli, Gioacchino, Bono, Luisa, Tortorici, Calogera, Manno, Audenzia, Benfante, Roberta, Li Cavoli, Tancredi Vincenzo, and Rotolo, Ugo

Abstract

Purpose: Calciphylaxis or Calcific Uraemic Arteriolopathy (CUA) is a rare systemic disorder associated with endstage renal disease and carrying a very poor prognosis and high mortality. It is characterized by skin necrosis and gangrene secondary to thrombosis and calcification of dermo-epidermal arterioles. Pathogenetic mechanisms inducing calciphylaxis are for the most part unknown. Methods: We report a case of calciphylaxis in a patient on long-term haemodialysis with severe secondary hyperparathyroidism. Despite therapies for hyperparathyroidism, the injury healed only after parathyroidectomy. Results: Calciphylaxis is an obliterative vasculopathy. The role of severe hyperparathyroidism in the pathogenesis of calciphylaxis is not well understood. A unique feature is the phenotypic differentiation of smooth muscle cells into osteoid-like cells. The vascular smooth muscle cells, exposed to high inorganic phosphate levels, could be transformed into osteoblast-like cells in patients undergoing haemodialysis with a poor control of phosphate intake. Conclusions: The uraemic condition contributes to vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Nowadays no effective treatments are available for the successful management of calciphylaxis., non disponibile

Published
2016

37. Calciphylaxis in chronic kidney disease

Author

Li Cavoli, Gioacchino, primary, Bono, Luisa, additional, Tortorici, Calogera, additional, Manno, Audenzia, additional, Benfante, Roberta, additional, Vincenzo Li Cavoli, Tancredi, additional, and Rotolo, Ugo, additional

Published
2016
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38. eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures

Author

Heise, Christopher, primary, Taha, Elham, additional, Murru, Luca, additional, Ponzoni, Luisa, additional, Cattaneo, Angela, additional, Guarnieri, Fabrizia C., additional, Montani, Caterina, additional, Mossa, Adele, additional, Vezzoli, Elena, additional, Ippolito, Giulio, additional, Zapata, Jonathan, additional, Barrera, Iliana, additional, Ryazanov, Alexey G., additional, Cook, James, additional, Poe, Michael, additional, Stephen, Michael Rajesh, additional, Kopanitsa, Maksym, additional, Benfante, Roberta, additional, Rusconi, Francesco, additional, Braida, Daniela, additional, Francolini, Maura, additional, Proud, Christopher G., additional, Valtorta, Flavia, additional, Passafaro, Maria, additional, Sala, Mariaelvina, additional, Bachi, Angela, additional, Verpelli, Chiara, additional, Rosenblum, Kobi, additional, and Sala, Carlo, additional

Published
2016
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39. α9- and α7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line.

Author

Mucchietto, Vanessa, Fasoli, Francesca, Pucci, Susanna, Moretti, Milena, Benfante, Roberta, Maroli, Annalisa, Di Lascio, Simona, Bolchi, Cristiano, Pallavicini, Marco, Dowell, Cheryl, McIntosh, Michael, Clementi, Francesco, and Gotti, Cecilia

Subjects
NICOTINIC acetylcholine receptors, ADENOCARCINOMA, CELL proliferation, CANCER cells, SMALL interfering RNA
Abstract

Background and Purpose: Tobacco smoke contains many classes of carcinogens and although nicotine is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis in lung tumours by acting on neuronal nicotinic ACh receptors (nAChRs). The aim of this study was to identify molecularly, biochemically and pharmacologically which nAChR subtypes are expressed and functionally activated by nicotine in lung cancer cell lines.Experimental Approach: We used A549 and H1975 adenocarcinoma cell lines derived from lung tumours to test the in vitro effects of nicotine, and nAChR subtype-specific peptides and compounds.Key Results: The two adenocarcinoma cell lines express distinctive nAChR subtypes, and this affects their nicotine-induced proliferation. In A549 cells, nAChRs containing the α7 or α9 subunits not only regulate nicotine-induced cell proliferation but also the activation of the Akt and ERK pathways. Blocking these nAChRs by means of subtype-specific peptides, or silencing their expression by means of subunit-specific siRNAs, abolishes nicotine-induced proliferation and signalling. Moreover, we found that the α7 antagonist MG624 also acts on α9-α10 nAChRs, blocks the effects of nicotine on A549 cells and has dose-dependent cytotoxic activity.Conclusions and Implications: These results highlight the pathophysiological role of α7- and α9-containing receptors in promoting non-small cell lung carcinoma cell growth and intracellular signalling and provide a framework for the development of new drugs that specifically target the receptors expressed in lung tumours.Linked Articles: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. [ABSTRACT FROM AUTHOR]

Published
2018
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40. Structural and functional differences in <italic>PHOX2B</italic> frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome.

Author

Di Lascio, Simona, Benfante, Roberta, Di Zanni, Eleonora, Cardani, Silvia, Adamo, Annalisa, Fornasari, Diego, Ceccherini, Isabella, and Bachetti, Tiziana

Abstract

Abstract: Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps (“frame 2” and “frame 3” mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one “frame 3” mutation identified in a patient with isolated CCHS, and one “frame 2” mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS. [ABSTRACT FROM AUTHOR]

Published
2018
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41. Nicotinic receptors increase cell proliferation and tumour progression in non-small cell lung cancer cell line

Author

Mucchietto, Vanessa, primary, Fasoli, Francesca, additional, Benfante, Roberta, additional, Maroli, Annalisa, additional, Cattaneo, M. Grazia, additional, Pistillo, Francesco, additional, Moretti, Milena, additional, Bolchi, Cristiano, additional, Pallavicini, Marco, additional, Clementi, Francesco, additional, and Gotti, Cecilia, additional

Published
2015
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