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10. Towards the standardization of mitochondrial proteomics: the Italian mt-HPP initiative

Author

Alberio, T., Pieroni, L., Ronci, M., Banfi, C., Bongarzone, I., Bottoni, P., Brioschi, M., Caterino, M., Chinello, C., Cormio, A., Cozzolino, F., Cunsolo, V., FONTANA, Simona, Garavaglia, B., Giusti, L., Greco, V., Lucacchini, A., Maffioli, E., Magni, F., Monteleone, Francesca, Monti, M., Monti, V., Musicco, C., Petrosillo, G., Porcelli, V., Saletti, R., Scatena, R., Soggiu, A., Tedeschi, G., Zilocchi, M., Roncada, P., Urbani, A., Fasano, M., Alberio, T, Pieroni, L, Ronci, M, Banfi, C, Bongarzone, I, Bottoni, P, Brioschi, M, Caterino, M, Chinello, C, Cormio, A, Cozzolino, F, Cunsolo, V, Fontana, S, Garavaglia, B, Giusti, L, Greco, V, Lucacchini, A, Maffioli, E, Magni, F, Monteleone, F, Monti, M, Monti, V, Musicco, C, Petrosillo, G, Porcelli, V, Saletti, R, Scatena, R, Soggiu, A, Tedeschi, G, Zilocchi, M, Roncada, P, Urbani, A, Fasano, M, Alberio, T., Pieroni, L., Ronci, M., Banfi, C., Bongarzone, I., Bottoni, P., Brioschi, M., Caterino, M., Chinello, C., Cormio, A., Cozzolino, F., Cunsolo, V., Fontana, S., Garavaglia, B., Giusti, L., Greco, V., Lucacchini, A., Maffioli, E., Magni, F., Monteleone, F., Monti, M., Monti, V., Musicco, C., Petrosillo, G., Porcelli, V., Saletti, R., Scatena, R., Soggiu, A., Tedeschi, G., Zilocchi, M., Roncada, P., Urbani, A., and Fasano, M.

Subjects
itlian mt-HPP iniziative, Mitochondria, standardization, enrichment protocol, Mitochondrial Human Proteome Project, mitochondrial proteomic, BIO/10 - BIOCHIMICA, proteomic
Abstract

The mitochondrial Human Proteome Project aims at understanding the function of the mitochondrial proteome and its crosstalk with the proteome of other organelles. Being able to choose a suitable and validated enrichment protocol of functional mitochondria, based on the specific needs of the downstream proteomics analysis, would greatly help the researchers in the field. Mitochondrial fractions from ten model cell lines were prepared using three enrichment protocols and analyzed on seven different LC-MS/MS platforms. All data were processed using neXtProt as reference database. The data are available for the Human Proteome Project purposes through the ProteomeXchange Consortium with the identifier PXD007053. The processed datasets were analysed using a suite of R routines to perform a statistical analysis and to retrieve subcellular and sub-mitochondrial localizations. Although the overall number of identified total and mitochondrial proteins was not significantly dependent on the enrichment protocol, specific line to line differences were observed. Moreover, the protein lists were mapped to a network representing the functional mitochondrial proteome, encompassing mitochondrial proteins and their first interactors. More than 80% of the identified proteins resulted nodes of this network but with a different ability in co-isolating mitochondria-associated structures for each enrichment protocol/cell line pair.

Published
2017

11. MIF/CD74 axis is a target for novel therapies in colon carcinomatosis

Author

Bozzi, F, Mogavero, A, Varinelli, L, Belfiore, A, Manenti, G, Caccia, C, Volpi, C, Beznoussenko, G, Milione, M, Leoni, V, Gloghini, A, Mironov, A, Leo, E, Pilotti, S, Pierotti, M, Bongarzone, I, Gariboldi, M, Volpi, CC, Beznoussenko, GV, Mironov, AA, Pierotti, MA, Bozzi, F, Mogavero, A, Varinelli, L, Belfiore, A, Manenti, G, Caccia, C, Volpi, C, Beznoussenko, G, Milione, M, Leoni, V, Gloghini, A, Mironov, A, Leo, E, Pilotti, S, Pierotti, M, Bongarzone, I, Gariboldi, M, Volpi, CC, Beznoussenko, GV, Mironov, AA, and Pierotti, MA

Abstract

Background: Strategies aimed at obtaining a complete cytoreduction are needed to improve long-term survival for patients with colorectal cancer peritoneal carcinomatosis (CRC-pc). Methods: We established organoid models from peritoneal metastases of two naïve CRC patients. A standard paraffin inclusion was conducted to compare their 3D structure and immunohistochemical profile with that of the corresponding surgical samples. RNA expression levels of the CRC stem cell marker LGR5 was measured by in situ hybridization. The secretome of organoids was profiled by mass spectrometry. Energy homeostasis of organoids was interfered with 4-IPP and metformin. Biochemical and metabolic changes after drug treatments were investigated by western blot and mass spectrometry. Mitochondria impairment was evaluated by electron microscopy and mitotraker staining. Results: The two organoids recapitulated their corresponding clinical samples in terms of 3D structure and immmunoistochemical profile and were positive for the cancer stem cells marker LGR5. Proteomic analyses of organoids highlighted their strong dependence on energy producing pathways, which suggest that their targeting could be an effective therapeutic approach. To test this hypothesis, we treated organoids with two drugs that target metabolism acting on AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis, which may act as metabolic tumour suppressor in CRC. Organoids were treated with 4-IPP, an inhibitor of MIF/CD74 signalling axis which activates AMPK function, or metformin that inhibits mitochondrial respiratory chain complex I. As a new finding we observed that treatment with 4-IPP downregulated AMPK signalling activity, reduced AKT phosphorylation and activated a JNK-mediated stress-signalling response, thus generating mitochondrial impairment and cell death. Metformin treatment enhanced AMPK activation, decreasing the activity of the anabolic factors ribosomal protein S6 and p4EBP

Published
2017

12. Towards the standardization of mitochondrial proteomics: the Italian mt-HPP initiative

Author

Alberio, T, Pieroni, L, Ronci, M, Banfi, C, Bongarzone, I, Bottoni, P, Brioschi, M, Caterino, M, Chinello, C, Cormio, A, Cozzolino, F, Cunsolo, V, Fontana, S, Garavaglia, B, Giusti, L, Greco, V, Lucacchini, A, Maffioli, E, Magni, F, Monteleone, F, Monti, M, Monti, V, Musicco, C, Petrosillo, G, Porcelli, V, Saletti, R, Scatena, R, Soggiu, A, Tedeschi, G, Zilocchi, M, Roncada, P, Urbani, A, Fasano, M, CHINELLO, CLIZIA, MAGNI, FULVIO, MONTI, MARIA GIOVANNA, Fasano, M., Alberio, T, Pieroni, L, Ronci, M, Banfi, C, Bongarzone, I, Bottoni, P, Brioschi, M, Caterino, M, Chinello, C, Cormio, A, Cozzolino, F, Cunsolo, V, Fontana, S, Garavaglia, B, Giusti, L, Greco, V, Lucacchini, A, Maffioli, E, Magni, F, Monteleone, F, Monti, M, Monti, V, Musicco, C, Petrosillo, G, Porcelli, V, Saletti, R, Scatena, R, Soggiu, A, Tedeschi, G, Zilocchi, M, Roncada, P, Urbani, A, Fasano, M, CHINELLO, CLIZIA, MAGNI, FULVIO, MONTI, MARIA GIOVANNA, and Fasano, M.

Abstract

The mitochondrial Human Proteome Project aims at understanding the function of the mitochondrial proteome and its crosstalk with the proteome of other organelles. Being able to choose a suitable and validated enrichment protocol of functional mitochondria, based on the specific needs of the downstream proteomics analysis, would greatly help the researchers in the field. Mitochondrial fractions from ten model cell lines were prepared using three enrichment protocols and analyzed on seven different LC-MS/MS platforms. All data were processed using neXtProt as reference database. The data are available for the Human Proteome Project purposes through the ProteomeXchange Consortium with the identifier PXD007053. The processed datasets were analysed using a suite of R routines to perform a statistical analysis and to retrieve subcellular and sub-mitochondrial localizations. Although the overall number of identified total and mitochondrial proteins was not significantly dependent on the enrichment protocol, specific line to line differences were observed. Moreover, the protein lists were mapped to a network representing the functional mitochondrial proteome, encompassing mitochondrial proteins and their first interactors. More than 80% of the identified proteins resulted nodes of this network but with a different ability in co-isolating mitochondria-associated structures for each enrichment protocol/cell line pair.

Published
2017

13. Toward the Standardization of Mitochondrial Proteomics: The Italian Mitochondrial Human Proteome Project Initiative

Author

Alberio, T., Pieroni, L., Ronci, M., Banfi, C., Bongarzone, I., Bottoni, P., Brioschi, M., Caterino, M., Chinello, C., Cormio, A., Cozzolino, F., Cunsolo, V., Fontana, S., Garavaglia, B., Giusti, L., Greco, Viviana, Lucacchini, A., Maffioli, E., Magni, F., Monteleone, F., Monti, M., Monti, V., Musicco, C., Petrosillo, G., Porcelli, V., Saletti, R., Scatena, Roberto, Soggiu, A., Tedeschi, G., Zilocchi, M., Roncada, P., Urbani, Andrea, Fasano, M., Greco V. (ORCID:0000-0003-4521-0020), Scatena R. (ORCID:0000-0002-9425-8293), Urbani A. (ORCID:0000-0001-9168-3174), Alberio, T., Pieroni, L., Ronci, M., Banfi, C., Bongarzone, I., Bottoni, P., Brioschi, M., Caterino, M., Chinello, C., Cormio, A., Cozzolino, F., Cunsolo, V., Fontana, S., Garavaglia, B., Giusti, L., Greco, Viviana, Lucacchini, A., Maffioli, E., Magni, F., Monteleone, F., Monti, M., Monti, V., Musicco, C., Petrosillo, G., Porcelli, V., Saletti, R., Scatena, Roberto, Soggiu, A., Tedeschi, G., Zilocchi, M., Roncada, P., Urbani, Andrea, Fasano, M., Greco V. (ORCID:0000-0003-4521-0020), Scatena R. (ORCID:0000-0002-9425-8293), and Urbani A. (ORCID:0000-0001-9168-3174)

Abstract

The Mitochondrial Human Proteome Project aims at understanding the function of the mitochondrial proteome and its crosstalk with the proteome of other organelles. Being able to choose a suitable and validated enrichment protocol of functional mitochondria, based on the specific needs of the downstream proteomics analysis, would greatly help the researchers in the field. Mitochondrial fractions from ten model cell lines were prepared using three enrichment protocols and analyzed on seven different LC-MS/MS platforms. All data were processed using neXtProt as reference database. The data are available for the Human Proteome Project purposes through the ProteomeXchange Consortium with the identifier PXD007053. The processed data sets were analyzed using a suite of R routines to perform a statistical analysis and to retrieve subcellular and submitochondrial localizations. Although the overall number of identified total and mitochondrial proteins was not significantly dependent on the enrichment protocol, specific line to line differences were observed. Moreover, the protein lists were mapped to a network representing the functional mitochondrial proteome, encompassing mitochondrial proteins and their first interactors. More than 80% of the identified proteins resulted in nodes of this network but with a different ability in coisolating mitochondria-associated structures for each enrichment protocol/cell line pair.

Published
2017

14. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype

Author

Santoro, M., Carlomagno, F., Hay, I. D., Herrmann, M. A., Grieco, M., Melillo, R., Marco Alessandro Pierotti, Bongarzone, I., Porta, G. D., Berger, N., Peix, J. L., Paulin, C., Fabien, N., Vecchio, G., Jenkins, R. B., Fusco, A., Santoro, Massimo, Carlomagno, Francesca, Hay, I. D., Herrmann, M. A., Grieco, M., Melillo, ROSA MARINA, Pierotti, M. A., Bongarzone, I., DELLA PORTA, G., Berger, N., Peix, J. L., Paulin, C., Fabien, N., Vecchio, Giancarlo, Jenkins, R. B., Fusco, Alfredo, Santoro, M, Carlomagno, F, Hay, Id, Herrmann, Ma, Grieco, Michele, Melillo, R, Pierotti, Ma, Bongarzone, I, Dellaporta, G, Berger, N, Peix, Jl, Paulin, C, Fabien, N, Vecchio, G, Jenkins, Rb, and Fusco, A.

Subjects
Pathology, endocrine system diseases, Restriction Mapping, Gene Expression, TYROSINE KINASE, Polymerase Chain Reaction, PROTO-ONCOGENE, Drosophila Proteins, RNA, Neoplasm, Gene Rearrangement, Thyroid, General Medicine, DNA, Neoplasm, Blotting, Southern, PTC, medicine.anatomical_structure, Cell Transformation, Neoplastic, Proto-Oncogene Proteins c-ret, Research Article, EXPRESSION, medicine.medical_specialty, endocrine system, CARCINOMA, TRANSFORMING GENE, Molecular Sequence Data, Biology, Transfection, SEQUENCE, Thyroid carcinoma, Proto-Oncogene Proteins, RAS GENE-MUTATIONS, RET PROTOONCOGENE, TUMORIGENESIS, medicine, Carcinoma, Humans, RNA, Messenger, Thyroid Neoplasms, RET/PTC Rearrangement, HIGH-FREQUENCY, Oncogene, Base Sequence, Cancer, Receptor Protein-Tyrosine Kinases, Gene rearrangement, Oncogenes, PROTOONCOGENE, medicine.disease, Carcinoma, Papillary, Cancer research, CARCINOMA CELL-LINE
Abstract

We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, papillary thyroid carcinoma (PTC), is a novel rearranged version of the ret tyrosine-kinase protooncogene. Thyroid neoplasms include a broad spectrum of malignant tumors, ranging from well-differentiated tumors to undifferentiated anaplastic carcinomas. To determine the frequency of ret oncogene activation, we analyzed 286 cases of human thyroid tumors of diverse histologic types. We found the presence of an activated form of the ret oncogene in 33 (19%) of 177 papillary carcinomas. By contrast, none of the other 109 thyroid tumors, which included 37 follicular, 15 anaplastic, and 18 medullary carcinomas, and 34 benign lesions, showed ret activation.

Published
1992

15. 4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

Author

Varinelli, L, Caccia, D, Volpi, C, Caccia, C, De Bortoli, M, Taverna, E, Gualeni, A, Leoni, V, Gloghini, A, Manenti, G, Bongarzone, I, Volpi, CC, Gualeni, AV, Varinelli, L, Caccia, D, Volpi, C, Caccia, C, De Bortoli, M, Taverna, E, Gualeni, A, Leoni, V, Gloghini, A, Manenti, G, Bongarzone, I, Volpi, CC, and Gualeni, AV

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is over-expressed in several human neoplastic cells. When MIF binds its receptor (CD74) and co-receptor (CD44), it initiates signaling cascades that orchestrate cell proliferation and survival, and it can directly modulate the activity of AMPK. These activities indicate that MIF potentially regulates cell survival and metabolism. We found that MIF was primarily co-expressed with CD74 in 16 out of 23 papillary thyroid carcinoma (PTC) and in all the 27 available anaplastic thyroid carcinoma (ATC) biopsy samples. MIF and CD74 were co-expressed in TPC-1 and HTC-C3 cell lines. The selective MIF inhibitor, 4-iodo-6- phenylpyrimidine (4-IPP), blocked MIF/CD74 internalization, activated JNK, and dosedependently inhibited proliferation inducing apoptosis and mitotic cell death. In two CD74-negative cell lines, NIM-1 and K1, 4-IPP treatment partially reduced proliferation. Coordinated MIF and CD74 expression appeared to confer in tumor cells the plasticity necessary to escape cell cycle regulation, metabolic changes, and stress conditions. MIF/CD74 signaling removal made cells susceptible to apoptosis and mitotic cell death. This finding suggests a possible avenue for targeting DNA endoreduplication, thus preventing the proliferation of therapy-resistant cell subpopulations. This study highlights MIF/CD74 axis as an important player in the biology of aggressive thyroid neoplasms.

Published
2015

16. Preliminary evidence on the diagnostic and molecular role of circulating soluble EGFR in non-small cell lung cancer

Author

Lococo, F, Paci, M, Rapicetta, C, Rossi, T, Sancisi, V, Braglia, L, Cavuto, S, Bisagni, A, Bongarzone, I, Noonan, D, Albini, A, Maramotti, S, Lococo, Filippo, Paci, Massimiliano, Rapicetta, Cristian, Rossi, Teresa, Sancisi, Valentina, Braglia, Luca, Cavuto, Silvio, Bisagni, Alessandra, Bongarzone, Italia, Noonan, Douglas M., Albini, Adriana, Maramotti, Sally, Lococo, F, Paci, M, Rapicetta, C, Rossi, T, Sancisi, V, Braglia, L, Cavuto, S, Bisagni, A, Bongarzone, I, Noonan, D, Albini, A, Maramotti, S, Lococo, Filippo, Paci, Massimiliano, Rapicetta, Cristian, Rossi, Teresa, Sancisi, Valentina, Braglia, Luca, Cavuto, Silvio, Bisagni, Alessandra, Bongarzone, Italia, Noonan, Douglas M., Albini, Adriana, and Maramotti, Sally

Abstract

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.

Published
2015

17. Preliminary evidence on the diagnostic and molecular role of circulating soluble EGFR in non-small cell lung cancer

Author

Lococo, Filippo, Paci, M., Rapicetta, C., Rossi, T., Sancisi, V., Braglia, L., Cavuto, S., Bisagni, A., Bongarzone, I., Noonan, D. M., Albini, A., Maramotti, S., Lococo F. (ORCID:0000-0002-9383-5554), Lococo, Filippo, Paci, M., Rapicetta, C., Rossi, T., Sancisi, V., Braglia, L., Cavuto, S., Bisagni, A., Bongarzone, I., Noonan, D. M., Albini, A., Maramotti, S., and Lococo F. (ORCID:0000-0002-9383-5554)

Abstract

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.

Published
2015

23. TUMOUR BIOLOGY

Author

Geller, T., primary, Prakash, V., additional, Batanian, J., additional, Guzman, M., additional, Duncavage, E., additional, Gershon, T., additional, Crowther, A., additional, Wu, J., additional, Liu, H., additional, Fang, F., additional, Davis, I., additional, Tripolitsioti, D., additional, Ma, M., additional, Kumar, K., additional, Grahlert, J., additional, Egli, K., additional, Fiaschetti, G., additional, Shalaby, T., additional, Grotzer, M., additional, Baumgartner, M., additional, Braoudaki, M., additional, Lambrou, G. I., additional, Giannikou, K., additional, Millionis, V., additional, Papadodima, S. A., additional, Settas, N., additional, Sfakianos, G., additional, Stefanaki, K., additional, Kattamis, A., additional, Spiliopoulou, C. A., additional, Tzortzatou-Stathopoulou, F., additional, Kanavakis, E., additional, Gholamin, S., additional, Mitra, S., additional, Feroze, A., additional, Zhang, M., additional, Esparza, R., additional, Kahn, S., additional, Richard, C., additional, Achrol, A., additional, Volkmer, A., additional, Liu, J., additional, Volkmer, J., additional, Majeti, R., additional, Weissman, I., additional, Cheshier, S., additional, Bhatia, K., additional, Brown, N., additional, Teague, J., additional, Lo, P., additional, Challis, J., additional, Beshay, V., additional, Sullivan, M., additional, Mechinaud, F., additional, Hansford, J., additional, Arifin, M. Z., additional, Dahlan, R. H., additional, Sobana, M., additional, Saputra, P., additional, Tisell, M. T., additional, Danielsson, A., additional, Caren, H., additional, Bhardwaj, R., additional, Chakravadhanula, M., additional, Hampton, C., additional, Ozals, V., additional, Georges, J., additional, Decker, W., additional, Kodibagkar, V., additional, Nguyen, A., additional, Legrain, M., additional, Gaub, M. P., additional, Pencreach, E., additional, Chenard, M. P., additional, Guenot, D., additional, Entz-Werle, N., additional, Kanemura, Y., additional, Ichimura, K., additional, Shofuda, T., additional, Nishikawa, R., additional, Yamasaki, M., additional, Shibui, S., additional, Arai, H., additional, Xia, J., additional, Brian, A., additional, Prins, R., additional, Pennell, C., additional, Moertel, C., additional, Olin, M., additional, Bie, L., additional, Zhang, X., additional, Olsson, M., additional, Kling, T., additional, Nelander, S., additional, Biassoni, V., additional, Bongarzone, I., additional, Verderio, P., additional, Massimino, M., additional, Magni, R., additional, Pizzamiglio, S., additional, Ciniselli, C., additional, Taverna, E., additional, De Bortoli, M., additional, Luchini, A., additional, Liotta, L., additional, Barzano, E., additional, Spreafico, F., additional, Visse, E., additional, Sanden, E., additional, Darabi, A., additional, Siesjo, P., additional, Jackson, S., additional, Cohen, K., additional, Lin, D., additional, Burger, P., additional, Rodriguez, F., additional, Yao, X., additional, Liucheng, R., additional, Qin, L., additional, Na, T., additional, Meilin, W., additional, Zhengdong, Z., additional, Yongjun, F., additional, Pfeifer, S., additional, Nister, M., additional, de Stahl, T. D., additional, Basmaci, E., additional, Orphanidou-Vlachou, E., additional, Brundler, M.-A., additional, Sun, Y., additional, Davies, N., additional, Wilson, M., additional, Pan, X., additional, Arvanitis, T., additional, Grundy, R., additional, Peet, A., additional, Eden, C., additional, Ju, B., additional, Phoenix, T., additional, Nimmervoll, B., additional, Tong, Y., additional, Ellison, D., additional, Lessman, C., additional, Taylor, M., additional, Gilbertson, R., additional, Folgiero, V., additional, del Bufalo, F., additional, Carai, A., additional, Cefalo, M. G., additional, Citti, A., additional, Rutella, S., additional, Locatelli, F., additional, Mastronuzzi, A., additional, Maher, O., additional, Khatua, S., additional, Zaky, W., additional, Lourdusamy, A., additional, Meijer, L., additional, Layfield, R., additional, Jones, D. T. W., additional, Capper, D., additional, Sill, M., additional, Hovestadt, V., additional, Schweizer, L., additional, Lichter, P., additional, Zagzag, D., additional, Karajannis, M. A., additional, Aldape, K. D., additional, Korshunov, A., additional, von Deimling, A., additional, Pfister, S., additional, Chakrabarty, A., additional, Feltbower, R., additional, Sheridon, E., additional, Hassan, H., additional, Shires, M., additional, Picton, S., additional, Hatziagapiou, K., additional, Tsorteki, F., additional, Bethanis, K., additional, Gemou-Engesaeth, V., additional, Chi, S. N., additional, Bandopadhayay, P., additional, Janeway, K., additional, Pinches, N., additional, Malkin, H., additional, Kieran, M. W., additional, Manley, P. E., additional, Green, A., additional, Goumnerova, L., additional, Ramkissoon, S., additional, Harris, M. H., additional, Ligon, K. L., additional, Kahlert, U., additional, Suarez, M., additional, Maciaczyk, J., additional, Bar, E., additional, Eberhart, C., additional, Kenchappa, R., additional, Krishnan, N., additional, Forsyth, P., additional, McKenzie, B., additional, Pisklakova, A., additional, McFadden, G., additional, Pan, W., additional, Rodriguez, L., additional, Glod, J., additional, Levy, J. M., additional, Thompson, J., additional, Griesinger, A., additional, Amani, V., additional, Donson, A., additional, Birks, D., additional, Morgan, M., additional, Handler, M., additional, Foreman, N., additional, Thorburn, A., additional, Lulla, R. R., additional, Laskowski, J., additional, Fangusaro, J., additional, DiPatri, A. J., additional, Alden, T., additional, Tomita, T., additional, Vanin, E. F., additional, Goldman, S., additional, Soares, M. B., additional, Remke, M., additional, Ramaswamy, V., additional, Wang, X., additional, Jorgensen, F., additional, Morrissy, A. S., additional, Marra, M., additional, Packer, R., additional, Bouffet, E., additional, Jabado, N., additional, Cole, B., additional, Rudzinski, E., additional, Anderson, M., additional, Bloom, K., additional, Lee, A., additional, Leary, S., additional, Leprivier, G., additional, Rotblat, B., additional, Agnihotri, S., additional, Kool, M., additional, Derry, B., additional, Taylor, M. D., additional, Sorensen, P. H., additional, Dobson, T., additional, Busschers, E., additional, Taylor, H., additional, Hatcher, R., additional, Lulla, R., additional, Rajaram, V., additional, Das, C., additional, and Gopalakrishnan, V., additional

Published
2014
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24. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC

Author

Pierotti, M. A., Santoro, M., Jenkins, R. B., Sozzi, G., Bongarzone, I., Grieco, M., Monzini, N., Miozzo, M., Herrmann, M. A., Alfredo Fusco, Hay, I. D., Porta, G. D., Vecchio, G., Pierotti, Ma, Santoro, M, Jenkins, Rb, Sozzi, G, Bongarzone, I, Grieco, Michele, Monzini, N, Miozzo, M, Herrmann, Ma, Fusco, A, Hay, Id, Dellaporta, G, and Vecchio, G.

Subjects
endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, Restriction Mapping, Locus (genetics), Chromosome Disorders, Biology, Polymerase Chain Reaction, Restriction map, Proto-Oncogene Proteins, Drosophila Proteins, Humans, Thyroid Neoplasms, Locus identified by probe H4, neoplasms, Chromosomal inversion, Chromosome Aberrations, Multidisciplinary, Chromosomes, Human, Pair 10, Hybridization probe, Breakpoint, Carcinoma, Proto-Oncogene Proteins c-ret, Chromosome, Receptor Protein-Tyrosine Kinases, Oncogenes, Molecular biology, Blotting, Southern, Chromosome Inversion, DNA Probes, Tyrosine kinase, Research Article
Abstract

RET/PTC is a transforming sequence created by the fusion of the tyrosine kinase domain of the RET protooncogene with the 5' end of the locus D10S170 designated by probe H4 and is frequently found activated in human papillary thyroid carcinomas. RET and D10S170 have been mapped to contiguous regions of the long arm of chromosome 10: q11.2 and q21, respectively. To identify the mechanism leading to the generation of the oncogenic sequence RET/PTC, a combined cytogenetic and molecular analysis of several cases of papillary thyroid carcinomas was done. In four cases the results indicated that these tumors had RET/PTC activation and a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with breakpoints coincident with the regions where RET and D10S170 are located. Therefore, a chromosome 10q inversion provides the structural basis for the D10S170-RET fusion that forms the hybrid transforming sequence RET/PTC.

Published
1992

25. RET receptor expression in thyroid follicular epithelial cell-derived tumors

Author

Bunone G, Uggeri M, Mondellini P, Marco Alessandro Pierotti, and Bongarzone I

Subjects
Platelet-Derived Growth Factor, Glial Cell Line-Derived Neurotrophic Factor Receptors, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Molecular Sequence Data, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Nerve Tissue Proteins, Sequence Analysis, DNA, Precipitin Tests, Proto-Oncogene Mas, Adenocarcinoma, Papillary, Proto-Oncogene Proteins, Adenocarcinoma, Follicular, Tumor Cells, Cultured, Drosophila Proteins, Humans, Glial Cell Line-Derived Neurotrophic Factor, Nerve Growth Factors, Thyroid Neoplasms, Phosphorylation
Abstract

The RET proto-oncogene encodes a receptor tyrosine kinase for transforming growth factor-beta-related neurotrophic factors, which include GDNF and neurturin. The expression of RET proto-oncogene was detected in several tissues, such as spleen, thymus, lymph nodes, salivary gland, and spinal cord, and in several neural crest-derived cell lines. RET expression in the thyroid gland was reported to be restricted to neural crest-derived C cells. The presence of RET mRNA or protein has not yet been reported in thyroid follicular cells. We previously demonstrated the expression of oncogenic rearranged versions of RET in papillary thyroid carcinomas: tumors derived from thyroid follicular cells. To assess the expression of the normal RET proto-oncogene in follicular cells, we analyzed its expression in a panel of neoplasias originating from thyroid follicular epithelial cells: papillary carcinomas and both follicular adenomas and carcinomas. We also demonstrated the presence of RET normal transcripts in two follicular thyroid carcinoma lymph node metastases. Moreover, we found the presence of the RET/ELE1 transcript, the reciprocal complementary form of the oncogenic fusion transcript ELE1/RET, in a papillary thyroid carcinoma specimen expressing the RET/PTC3 oncogene, thus demonstrating that the RET promoter is active in those cells after rearrangement. Finally, we show that in a papillary carcinoma-derived cell line expressing the proto-RET receptor and the related GFRalpha2 co-receptor, GDNF treatment induced RET tyrosine phosphorylation and subsequent signal transduction pathway, indicating that RET could be active in thyroid follicular cells.

Published
2000

26. SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling.

Author

Donatello, Simona, Fiorino, A, Degl'Innocenti, D, Alberti, Luisella, Miranda, C, Gorla, L, Bongarzone, I, Rizzetti, M G, Pierotti, M A, Borrello, M G, Donatello, Simona, Fiorino, A, Degl'Innocenti, D, Alberti, Luisella, Miranda, C, Gorla, L, Bongarzone, I, Rizzetti, M G, Pierotti, M A, and Borrello, M G

Abstract

The RET gene encodes two main isoforms of a receptor tyrosine kinase (RTK) implicated in various human diseases. Activating germ-line point mutations are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinomas, inactivating germ-line mutations for Hirschsprung's disease, while somatic rearrangements (RET/PTCs) are specific to papillary thyroid carcinomas. SH2B1beta, a member of the SH2B adaptors family, and binding partner for several RTKs, has been recently described to interact with proto-RET. Here, we show that both RET isoforms and its oncogenic derivatives bind to SH2B1beta through the SRC homology 2 (SH2) domain and a kinase activity-dependent mechanism. As a result, RET phosphorylates SH2B1beta, which in turn enhances its autophosphorylation, kinase activity, and downstream signaling. RET tyrosine residues 905 and 981 are important determinants for functional binding of the adaptor, as removal of both autophosphorylation sites displaces its recruitment. Binding of SH2B1beta appears to protect RET from dephosphorylation by protein tyrosine phosphatases, and might represent a likely mechanism contributing to its upregulation. Thus, overexpression of SH2B1beta, by enhancing phosphorylation/activation of RET transducers, potentiates the cellular differentiation and the neoplastic transformation thereby induced, and counteracts the action of RET inhibitors. Overall, our results identify SH2B1beta as a key enhancer of RET physiologic and pathologic activities., Journal Article, info:eu-repo/semantics/published

Published
2007

27. Loss of function effect of RET mutations causing Hirschsprung disease

Author

Pasini, B, Borrello, Mg, Greco, A, Bongarzone, I, Luo, Y, Mondellini, P, Alberti, L, Miranda, C, Arighi, E, Bocciardi, Renata, Seri, M, Barone, V, Radice, Mt, Romeo, G, LOSS OF FUNCTION EFFECT OF RET MUTATIONS, PIEROTTI M., and May, CAUSING HIRSCHSPRUNG D. I. S. E. A. S. E. NAT G. E. N. E. T.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, endocrine system diseases, Hirschsprung disease, Recombinant Fusion Proteins, Cellular differentiation, Molecular Sequence Data, RET proto-oncogene, Biology, Transfection, PC12 Cells, loss-of-function, Mice, chemistry.chemical_compound, Exon, Proto-Oncogene Proteins, Genetics, Animals, Drosophila Proteins, Humans, Phosphorylation, neoplasms, Loss function, Base Sequence, Genetic Complementation Test, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Cell Differentiation, Tyrosine phosphorylation, 3T3 Cells, Exons, Cyclic AMP-Dependent Protein Kinases, Precipitin Tests, Rats, Cell Transformation, Neoplastic, chemistry, Mutation, Mutagenesis, Site-Directed, Cancer research, Tyrosine, RET, Tyrosine kinase, HeLa Cells
Abstract

We have introduced three Hirschsprung (HSCR) mutations localized in the tyrosine kinase domain of RET into the RET/PTC2 chimaeric oncogene which is capable of transforming NIH3T3 mouse fibroblasts and of differentiating pC12 rat pheochromocytoma cells. The three HSCR mutations abolished the biological activity of RET/PTC2 in both cell types and significantly decreased its tyrosine phosphorylation. By contrast, a rare polymorphism in exon 18 does not alter the transforming capability of RET/PTC2 or its tyrosine phosphorylation. These data suggest a loss of function effect of HSCR mutations which might act through a dominant negative mechanism. Our model system is therefore capable of discriminating between causative HSCR mutations and rare polymorphisms in the tyrosine kinase domain of RET.

Published
1995

28. Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas

Author

Bongarzone I, Mg, Butti, Coronelli S, Mg, Borrello, Santoro M, Mondellini P, Pilotti S, Fusco A, Della Porta G, Marco Alessandro Pierotti, I., Bongarzone, M. G., Butti, S., Coronelli, M. G., Borrello, Santoro, Massimo, P., Mondellini, S., Pilotti, Fusco, Alfredo, G., Dellaporta, and M. A., Pierotti

Subjects
Gene Rearrangement, Base Sequence, Molecular Sequence Data, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, 3T3 Cells, DNA, Neoplasm, Sequence Analysis, DNA, Carcinoma, Papillary, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Mice, Cell Transformation, Neoplastic, Proto-Oncogene Proteins, Proto-Oncogenes, Animals, Drosophila Proteins, Humans, Amino Acid Sequence, Thyroid Neoplasms, Cloning, Molecular
Abstract

Tumor specific rearrangements of ret gene are frequently detected in papillary thyroid carcinomas. These rearrangements result in the formation of chimeric genes showing the tyrosine kinase domain of ret fused with the 5' end sequences of different genes. We examined a series of 52 patients and identified 10 cases of ret fusion with D10S170 locus resulting in the generation of ret/PTC1 oncogene, 2 cases with the gene encoding the regulatory subunit RI alpha of PKA (ret/PTC2), and finally 6 cases, here described, with a newly discovered gene called ele1 localized on chromosome 10 and leading to the formation of ret/PTC3 oncogene. Our results show the expression of the ret/PTC3 hybrid gene in all the 6 cases and demonstrated its association with the synthesis of 2 constitutively phosphorylated isoforms of the oncoprotein (p75 and p80). The chromosome 10 localization of both ret and ele1 and the detection, in all cases, of a sequence reciprocal to that generating the oncogenic rearrangements, strongly suggest that ret/PTC3 formation is a consequence of an intrachromosomal inversion of chromosome 10.

Published
1994

31. Pediatrics Clinical Research

Author

Wrede, B., primary, Peters, O., additional, Kordes, U., additional, Kutluk, T., additional, Hasselblatt, M., additional, Rytting, M., additional, Rutkowski, S., additional, Mahajan, A., additional, Pietsch, T., additional, Thall, P., additional, Wolff, J. E., additional, Pfister, S., additional, Bingham, R., additional, Vats, T., additional, Rokes, C., additional, Brown, R., additional, Creach, K. M., additional, Rubin, J. B., additional, Leonard, J. R., additional, Limbrick, D. D., additional, Smyth, M. D., additional, Dacey, R. G., additional, Rich, K. M., additional, Dowling, J. L., additional, Linette, G. P., additional, King, A. A., additional, Michalski, J. M., additional, Simpson, J. R., additional, Park, T. S., additional, Perry, A., additional, Mansur, D. B., additional, Gururangan, S., additional, Panandikar, A. P., additional, Broniscer, A., additional, Huang, A., additional, Kellie, S., additional, Ellison, D., additional, Gajjar, A., additional, Aguilera, D., additional, Goldman, S., additional, Tomita, T., additional, Fangusaro, J., additional, Poussaint, T. Y., additional, Onar, A., additional, Gilbertson, R., additional, Packer, R., additional, McClendon, R., additional, Friedman, H., additional, Boyett, J., additional, Baker, J. N., additional, Tagen, M., additional, Onar-Thomas, A., additional, Gilbertson, R. J., additional, Davidoff, A. M., additional, Pai-Panandiker, A., additional, Leung, W., additional, Chin, T. K., additional, Stewart, C. F., additional, Kocak, M., additional, Rowland, C., additional, Merchant, T. E., additional, Kaste, S., additional, Allen, J., additional, Donahue, B., additional, Mathew, J., additional, Kretschmar, C., additional, Pollack, I., additional, Jakacki, R., additional, Massimino, M., additional, Biassoni, V., additional, Gandola, L., additional, Ferroli, P., additional, Bongarzone, I., additional, Spreafico, F., additional, Pecori, E., additional, Schiavello, E., additional, Modena, P., additional, Bach, F., additional, Potepan, P., additional, Slavc, I., additional, Peyrl, A., additional, Czech, T., additional, Haberler, C., additional, Dieckmann, K., additional, Brown, R. J., additional, Dhall, G., additional, Marachelian, A., additional, Gozali, A., additional, Butturini, A., additional, Gilles, F., additional, Thompson, S. J., additional, Gardner, S., additional, Finlay, J. L., additional, Eisenstat, D. D., additional, and Evans, A., additional

Published
2010
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36. trk andret proto-oncogene expression in human neuroblastoma specimens: High frequency oftrk expression in non-advanced stages

Author

Borrello, M. G., primary, Bongarzone, I., additional, Plerotti, M. A., additional, Luksch, R., additional, Gasparini, M., additional, Collini, P., additional, Pllotti, S., additional, Rlzzetti, M. G., additional, Mondellini, P., additional, De Bernardi, B., additional, Di Martino, D., additional, Garaventa, A., additional, Brisigotti, M., additional, and Tonini, G. P., additional

Published
1993
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40. Tyrosines outside the kinase core and dimerization are required for the mitogenic activity of RET/ptc2.

Author

Durick, K, Yao, V J, Borrello, M G, Bongarzone, I, Pierotti, M A, and Taylor, S S

Abstract

Defects in the c-ret proto-oncogene, a member of the protein tyrosine kinase receptor family, have recently been linked to two types of genetic syndromes, Hirschsprung's disease and the multiple endocrine neoplasia family of inherited cancers. RET/ptc2 is the product of a papillary thyroid carcinoma translocation event between the genes coding for c-ret and the type I alpha regulatory subunit of protein kinase A (RI alpha) (Lanzi, C., Borrello, M., Bongarzone, I., Migliazza, A., Fusco, A., Grieco, M., Santoro, M., Gambetta, R., Zunino, F., Della Porta, G., and Pierotti, M. (1992) Oncogene 7, 2189-2194). The resulting 596-residue protein contains the first two-thirds of RI alpha and the entire tyrosine kinase domain of c-ret (RETtk). An in vivo assay of growth stimulatory effects was developed, which consisted of microinjecting a RET/ptc2 expression plasmid into the nuclei of 10T1/2 mouse fibroblasts and observing the incorporation of 5-bromodeoxyuridine. This assay was used to determine that only the dimerization domain of RI alpha fused to RETtk is required for RET/ptc2's mitogenic activity. In addition, all of the reported Hirschsprung's disease point mutations in the RETtk (S289P, R421Q, and R496G) inactivate RET/ptc2 in our assay, confirming that these are loss of function mutations. Two tyrosines outside the conserved kinase core were also identified that are essential for full mitogenic activity of RET/ptc2. These two tyrosines, Tyr-350 and Tyr-586, are potential sites for Src homology 2 and phosphotyrosine binding domain interactions.

Published
1995

45. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features

Author

Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, and Marco Alessandro Pierotti

Subjects
Adult, Aged, 80 and over, Gene Rearrangement, Male, Adolescent, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Receptors, Nerve Growth Factor, Middle Aged, Carcinoma, Papillary, Child, Preschool, Proto-Oncogene Proteins, Drosophila Proteins, Humans, Female, Thyroid Neoplasms, Receptor, trkA, Child, Aged
Abstract

The papillary carcinoma family (PCF) of thyroid tumors includes a wide variety of neoplastic entities regarded as well-differentiated, poorly differentiated, and undifferentiated papillary thyroid carcinomas. Recent studies have established the presence of alternative oncogenic rearrangements of the RET and NTRK1 genes in a consistent fraction (or = 50%) of papillary thyroid tumors. RET oncogenic rearrangements are also very frequent (approximately 60%) in Chernobyl radiation-associated papillary thyroid neoplasias, which show an increased aggressiveness in terms of pathological stage at disease onset. These observations prompted us to study the relationship between the presence or absence of RET and NTRK1 oncogenes and the clinicopathological features (age, sex, histopathology, and pTNMC2 staging) of 76 consecutive, non-radiation-related tumors of the PCF. As previously reported, statistical univariate analysis revealed a correlation between the combination of RET and NTRK1 (RET/NTRK1) positivity and young age of patients at diagnosis. In addition, a significant association was found between RET/NTRK1 positivity and locally advanced stage of disease at presentation (pT4: P0.015). The multivariate analysis confirmed that RET/NTRK1 activation parallels an unfavorable disease presentation, which may correlate with a less favorable disease outcome. Furthermore, within the PCF, the frequency of RET/NTRK1 positivity was not influenced by the different neoplastic subtypes or the tumor versus degree of differentiation.

46. Human TRK proto-oncogene maps to chromosome 1q32-q41

Author

Miozzo, M., Marco Alessandro Pierotti, Sozzi, G., Radice, P., Bongarzone, I., Spurr, N. K., and Della Porta, G.

Subjects
Blotting, Southern, Chromosomes, Human, Pair 1, Proto-Oncogenes, Chromosome Mapping, Humans, Protein-Tyrosine Kinases, DNA Probes, Proto-Oncogene Mas
Abstract

The chromosomal localization of TRK, a gene coding for a putative receptor molecule with an associated tyrosine kinase activity that we have found activated in 25% of patients with papillary thyroid carcinoma, was determined by Southern blot analysis of a panel of human-rodent somatic cells using a cDNA clone containing the entire human TRK proto-oncogene (Martin-Zanca et al., 1986). The TRK gene was assigned to chromosome 1. One hybrid that had retained only the short arm of the human chromosome 1 was negative. Subsequently, in situ hybridization of the same probe to human metaphase chromosomes localized the TRK gene to 1q32-q41.

48. DNA Methylation Affecting the Transforming Activity of the Human Ha-ras Oncogene

Author

Mg, Borrello, Marco Alessandro Pierotti, Bongarzone I, Donghi R, Mondellini P, and Della Porta G

Subjects
Mice, Cell Transformation, Neoplastic, Base Sequence, Azacitidine, Animals, Humans, DNA, Oncogenes, Transfection, Methylation, Cells, Cultured, Plasmids
Abstract

A plasmid containing the transforming Ha-ras gene and designated pT24-C3 was methylated in vitro using the sequence-specific bacterial methyltransferases HpaII and HhaI. Aliquots of the plasmid were methylated by the single enzymes or by the two enzymes simultaneously (double methylation). The transforming activity of the treated plasmids was assayed in the standard transfection assay on NIH-3T3 cells. Double methylation reduced the transforming activity of pT24-C3 about 80%, whereas treatment with the single methylating enzymes did not significantly affect the oncogene activity. Southern blot analysis of the transformants obtained with the methylated or mock-methylated pT24-C3 plasmids indicated in all the examined DNAs the presence of human Ha-ras sequences with methylation degrees consistent with the treatment of the plasmids. The Mr 21,000 oncogene protein p21 was also detected in several examined transformants. The DNA-demethylating agent 5-azacytidine restored the transforming activity of the double-methylated pT24-C3 upon 24 h incubation of transfected NIH-3T3 cells. Southern blot analysis showed integration of human Ha-ras with a methylation profile intermediate between the double-methylated and mock-methylated plasmids. It is suggested that DNA methylation of specific CG-containing target sites can affect the transforming activity of a human oncogene.

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