MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis.
Rescue of embryonic lethality in MDM4(-/-) mice through concomitant loss of p53 has revealed a functional partnership between the two proteins. Biochemical studies have suggested that MDM4 may act as a negative regulator of p53 levels and activity. On the other hand, MDM4 overexpression has been reported to stabilize p53 levels and to counteract MDM2-degradative activity. We have investigated the functional role of MDM4 overexpression on cell behavior. In both established and primary cells cultured under stress conditions, overexpression of MDM4 significantly increased p53-dependent cell death, in correlation with enhanced induction of the endogenous p53 protein levels. This phenomenon was associated with induced p53 transcriptional activity and increased levels of the proapoptotic protein, Bax. Further, p53 stabilization was accompanied by decreased association of the protein to its negative regulator, MDM2. These findings reveal a novel role for MDM4 by demonstrating that in non-tumor cells under stress conditions it may act as a positive regulator of p53 activity, mainly by controlling p53 levels. They also indicate a major distinction between the biological consequences of MDM4 and MDM2 overexpression.
Mancini
Francesca
F
Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, Rome 00158, Italy.
Gentiletti
Francesca
F
D'Angelo
Marco
M
Giglio
Simona
S
Nanni
Simona
S
D'Angelo
Carmen
C
Farsetti
Antonella
A
Citro
Gennaro
G
Sacchi
Ada
A
Pontecorvi
Alfredo
A
Moretti
Fabiola
F
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D016895:Culture Media, Serum-Free; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004355:Drug Stability; D015870:Gene Expression; D006801:Humans; D007163:Immunosorbent Techniques; D020287:In Situ Nick-End Labeling; D051379:Mice; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D016895:Culture Media, Serum-Free; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D004247:DNA; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)