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3. P53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes

Author

Prodosmo, Andrea, De Amicis, Andrea, Nistico, Cecilia, Gabriele, Mario, Di Rocco, Giuliana, Monteonofrio, Laura, Piane, Maria, Cundari, Enrico, Chessa, Luciana, and Soddu, Silvia

Subjects
Gene mutations -- Physiological aspects -- Research, Ataxia telangiectasia -- Genetic aspects -- Diagnosis -- Care and treatment -- Research, Genetic screening -- Usage, Health care industry
Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but [...]

Published
2013
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8. Additional file 1: of Erratum to: Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Author

Prodosmo, Andrea, Buffone, Amelia, Mattioni, Manlio, Barnabei, Agnese, Persichetti, Agnese, Leo, Aurora De, Appetecchia, Marialuisa, Nicolussi, Arianna, Coppa, Anna, Sciacchitano, Salvatore, Giordano, Carolina, Pinnarò, Paola, Sanguineti, Giuseppe, Strigari, Lidia, Alessandrini, Gabriele, Facciolo, Francesco, Cosimelli, Maurizio, Grazi, Gian, Corrado, Giacomo, Vizza, Enrico, Giannini, Giuseppe, and Soddu, Silvia

Abstract

Characteristics of ATM variants. (DOCX 16 kb)

Published
2019
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9. Erratum to: Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Author

Prodosmo, Andrea, primary, Buffone, Amelia, additional, Mattioni, Manlio, additional, Barnabei, Agnese, additional, Persichetti, Agnese, additional, De Leo, Aurora, additional, Appetecchia, Marialuisa, additional, Nicolussi, Arianna, additional, Coppa, Anna, additional, Sciacchitano, Salvatore, additional, Giordano, Carolina, additional, Pinnarò, Paola, additional, Sanguineti, Giuseppe, additional, Strigari, Lidia, additional, Alessandrini, Gabriele, additional, Facciolo, Francesco, additional, Cosimelli, Maurizio, additional, Grazi, Gian Luca, additional, Corrado, Giacomo, additional, Vizza, Enrico, additional, Giannini, Giuseppe, additional, and Soddu, Silvia, additional

Published
2016
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10. Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Author

Prodosmo, Andrea, primary, Buffone, Amelia, additional, Mattioni, Manlio, additional, Barnabei, Agnese, additional, Persichetti, Agnese, additional, De Leo, Aurora, additional, Appetecchia, Marialuisa, additional, Nicolussi, Arianna, additional, Coppa, Anna, additional, Sciacchitano, Salvatore, additional, Giordano, Carolina, additional, Pinnarò, Paola, additional, Sanguineti, Giuseppe, additional, Strigari, Lidia, additional, Alessandrini, Gabriele, additional, Facciolo, Francesco, additional, Cosimelli, Maurizio, additional, Grazi, Gian Luca, additional, Corrado, Giacomo, additional, Vizza, Enrico, additional, Giannini, Giuseppe, additional, and Soddu, Silvia, additional

Published
2016
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12. MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway.

Author

Mancini, F, Di Conza, G, Pellegrino, M, Rinaldo, C, Prodosmo, Andrea, Giglio, Simona, D'Agnano, I, Florenzano, F, Felicioni, L, Buttitta, F, Marchetti, A, Sacchi, A, Pontecorvi, Alfredo, Soddu, S, Moretti, Fabiola, Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865), Mancini, F, Di Conza, G, Pellegrino, M, Rinaldo, C, Prodosmo, Andrea, Giglio, Simona, D'Agnano, I, Florenzano, F, Felicioni, L, Buttitta, F, Marchetti, A, Sacchi, A, Pontecorvi, Alfredo, Soddu, S, Moretti, Fabiola, and Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865)

Abstract

MDM4 is a key regulator of p53, whose biological activities depend on both transcriptional activity and transcription-independent mitochondrial functions. MDM4 binds to p53 and blocks its transcriptional activity; however, the main cytoplasmic localization of MDM4 might also imply a regulation of p53-mitochondrial function. Here, we show that MDM4 stably localizes at the mitochondria, in which it (i) binds BCL2, (ii) facilitates mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46(P)) and (iii) promotes binding between p53Ser46(P) and BCL2, release of cytochrome C and apoptosis. In agreement with these observations, MDM4 reduction by RNA interference increases resistance to DNA-damage-induced apoptosis in a p53-dependent manner and independently of transcription. Consistent with these findings, a significant downregulation of MDM4 expression associates with cisplatin resistance in human ovarian cancers, and MDM4 modulation affects cisplatin sensitivity of ovarian cancer cells. These data define a new localization and function of MDM4 that, by acting as a docking site for p53Ser46(P) to BCL2, facilitates the p53-mediated intrinsic-apoptotic pathway. Overall, our results point to MDM4 as a double-faced regulator of p53.

Published
2009

14. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization

Author

Giglio, Simona, Mancini, F, Gentiletti, F, Sparaco, G, Felicioni, L, Barassi, F, Martella, C, Prodosmo, Andrea, Iacovelli, S, Buttitta, F, Farsetti, Antonella, Soddu, S, Marchetti, A, Sacchi, A, Pontecorvi, Alfredo, Moretti, Fabiola, Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865), Giglio, Simona, Mancini, F, Gentiletti, F, Sparaco, G, Felicioni, L, Barassi, F, Martella, C, Prodosmo, Andrea, Iacovelli, S, Buttitta, F, Farsetti, Antonella, Soddu, S, Marchetti, A, Sacchi, A, Pontecorvi, Alfredo, Moretti, Fabiola, and Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865)

Abstract

The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact. Several oncogenic forms derived from splicing of HDM2 have been described in cancer. This work aimed at investigating whether analogous forms of HDMX exist in human tumors. Here, we report the characterization of an aberrantly spliced form of HDMX, HDMX211, isolated from the thyroid tumor cell line, ARO. HDMX211 binds and stabilizes the HDM2 protein. Although it lacks the p53 binding domain, HDMX211 also stabilizes p53 by counteracting its degradation by HDM2. However, the resulting p53 is transcriptionally inactive and increasingly associated to its inhibitor HDM2. Expression of HDMX211 strongly enhances the colony-forming ability of human cells in the presence or absence of wild-type p53. Conversely, depletion of HDMX211 by small interfering RNA significantly reduces the growth of ARO cells and increases their sensitivity to chemotherapy. Screening of lung cancer biopsies shows the presence of HDMX211 in samples that overexpress HDM2 protein, supporting a pathologic role for this new protein. This is the first evidence of a variant form of HDMX that has oncogenic potential independently of p53. HDMX211 reveals a new mechanism for overexpression of the oncoprotein HDM2. Most interestingly, it outlines a possible molecular explanation for a yet unclarified tumor phenotype, characterized by simultaneous overexpression of HDM2 and wild-type p53.

Published
2005

15. MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Author

Petroni, Marialaura, primary, Veschi, Veronica, additional, Prodosmo, Andrea, additional, Rinaldo, Cinzia, additional, Massimi, Isabella, additional, Carbonari, Maurizio, additional, Dominici, Carlo, additional, McDowell, Heather P., additional, Rinaldi, Christian, additional, Screpanti, Isabella, additional, Frati, Luigi, additional, Bartolazzi, Armando, additional, Gulino, Alberto, additional, Soddu, Silvia, additional, and Giannini, Giuseppe, additional

Published
2011
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18. Identification of an Aberrantly Spliced Form of HDMX in Human Tumors: A New Mechanism for HDM2 Stabilization

Author

Giglio, Simona, primary, Mancini, Francesca, additional, Gentiletti, Francesca, additional, Sparaco, Giorgia, additional, Felicioni, Lara, additional, Barassi, Fabio, additional, Martella, Carla, additional, Prodosmo, Andrea, additional, Iacovelli, Stefano, additional, Buttitta, Fiamma, additional, Farsetti, Antonella, additional, Soddu, Silvia, additional, Marchetti, Antonio, additional, Sacchi, Ada, additional, Pontecorvi, Alfredo, additional, and Moretti, Fabiola, additional

Published
2005
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