MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway.
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.
Mancini
Francesca
F
Institute of Neurobiology and Molecular Medicine, National Council of Research, Rome, Italy.
Di Conza
Giusy
G
Pellegrino
Marsha
M
Rinaldo
Cinzia
C
Prodosmo
Andrea
A
Giglio
Simona
S
D'Agnano
Igea
I
Florenzano
Fulvio
F
Felicioni
Lara
L
Buttitta
Fiamma
F
Marchetti
Antonio
A
Sacchi
Ada
A
Pontecorvi
Alfredo
A
Soddu
Silvia
S
Moretti
Fabiola
F
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C052617:Bcl2 protein, mouse; D045304:Cytochromes c; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin