MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts. (Articolo in rivista)

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  • MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts. (Articolo in rivista) (literal)
Anno
  • 2002-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1038/sj.onc.1205137 (literal)
Alternative label
  • Gentiletti F., Mancini F., Pontecorvi A., Sacchi A., Jochemsen A.G., Moretti F. (2002)
    MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts.
    in Oncogene (Basingstoke)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Gentiletti F., Mancini F., Pontecorvi A., Sacchi A., Jochemsen A.G., Moretti F. (literal)
Pagina inizio
  • 867 (literal)
Pagina fine
  • 877 (literal)
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  • 21 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 11 (literal)
Note
  • PubMe (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • [ 1 ] Regina Elena Inst Canc Res, Mol Oncogenesis Lab, I-00158 Rome, Italy [ 2 ] Catholic Univ, Med Pathol Inst, I-00100 Rome, Italy [ 3 ] Leiden Univ, Ctr Med, Dept Mol & Cell Biol, NL-2300 RA Leiden, Netherlands [ 4 ] CNR, Neurobiol & Mol Med Inst, I-00156 Rome, Italy (literal)
Titolo
  • MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts. (literal)
Abstract
  • MDMX is a p53 binding protein, which shares a high degree of homology with MDM2, a negative regulator of the tumor suppressor p53. MDMX has been shown to counteract MDM2-dependent p53 degradation and to stabilize p53 in its inactive form. In this study we identify two MDMX proteolytic pathways that control its intracellular levels, and show that MDMX posttranslational processing may be regulated by p53. Mouse MDMX is cleaved in vitro and in vivo by caspase activity, between aminoacids 358 and 361, producing a p54 minor form. In addition, MDMX is subjected to proteasome-mediated degradation, which concurs to MDMX proteolysis mainly through degradation of p54. A D361A-MDMX mutant, resistant to caspase cleavage, exhibits prolonged intracellular lifetime in comparison to wild- type protein, indicating that caspase cleavage affects stability of MDMX protein probably by modulating its further degradation. Overexpression of exogenous p53 increases the intracellular levels of p54 product. Similarly, activation of endogenous p53 by adriamycin enhances MDMX cleavage and produces a marked decrease of its intracellular levels, while not affecting the D361A-MDMX mutant. In addition, the D361A-MDMX mutant lacks the ability to inhibit p53 transactivation in respect to wild-type MDMX, suggesting that MDMX caspase cleavage play an important functional role. In conclusion, our results demonstrate that, in analogy to MDM2, MDMX may be subjected to proteolytic modifications that regulate its intracellular levels. Moreover, decrease of MDMX protein levels following p53 activation suggests a p53-dependent regulatory feedback of MDMX function. (literal)
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