MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic apoptotic pathway (Articolo in rivista)

Type
Label
  • MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic apoptotic pathway (Articolo in rivista) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1038/emboj.2009.154 (literal)
Alternative label
  • Mancini F.1,2, Di Conza G.1,3, Pellegrino M.1, Rinaldo C.4, Prodosmo A. 2,4, Giglio S. 1,2, D'Agnano I. 1, Florenzano F.5, Felicioni L. 6, Buttitta F. 6, Marchetti A. 6, Sacchi A. 4, Pontecorvi A. 2, Soddu S. 4, Moretti F. 1 (2009)
    MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic apoptotic pathway
    in EMBO journal (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Mancini F.1,2, Di Conza G.1,3, Pellegrino M.1, Rinaldo C.4, Prodosmo A. 2,4, Giglio S. 1,2, D'Agnano I. 1, Florenzano F.5, Felicioni L. 6, Buttitta F. 6, Marchetti A. 6, Sacchi A. 4, Pontecorvi A. 2, Soddu S. 4, Moretti F. 1 (literal)
Pagina inizio
  • 1926 (literal)
Pagina fine
  • 1939 (literal)
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  • Epub 2009 Jun 11 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
  • http://www.nature.com/emboj/journal/v28/n13/pdf/emboj2009154a.pdf (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 28 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 13 (literal)
Note
  • PubMe (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 1 - Institute of Neurobiology and Molecular Medicine, National Council of Research, Rome, Italy; 2 - Division of Endocrinology, Catholic University, Rome, Italy; 3 - Department of Experimental-Clinical Medicine and Pharmacology, University of Messina, Messina, Italy; 4 - Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, Italy; 5 - Confocal Microscopy Unit, EBRI-CNR-Fondazione Santa Lucia, Rome, Italy; 6 - Clinical Research Center, University-Foundation 'G D'Annunzio', Chieti, Italy (literal)
Titolo
  • MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic apoptotic pathway (literal)
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 (p53Ser46P) and (iii) promotes binding between p53Ser46P 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 p53Ser46P to BCL2, facilitates the p53-mediated intrinsic-apoptotic pathway. Overall, our results point to MDM4 as a double-faced regulator of p53. (literal)
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