Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity.
Human tumors are believed to harbor a disabled p53 tumor suppressor pathway, either through direct mutation of the p53 gene or through aberrant expression of proteins acting in the p53 pathway, such as p14(ARF) or Mdm2. A role for Mdmx (or Mdm4) as a key negative regulator of p53 function in vivo has been established. However, a direct contribution of Mdmx to tumor formation remains to be demonstrated. Here we show that retrovirus-mediated Mdmx overexpression allows primary mouse embryonic fibroblast immortalization and leads to neoplastic transformation in combination with HRas(V12). Furthermore, the human Mdmx ortholog, Hdmx, was found to be overexpressed in a significant percentage of various human tumors and amplified in 5% of primary breast tumors, all of which retained wild-type p53. Hdmx was also amplified and highly expressed in MCF-7, a breast cancer cell line harboring wild-type p53, and interfering RNA-mediated reduction of Hdmx markedly inhibited the growth potential of these cells in a p53-dependent manner. Together, these results make Hdmx a new putative drug target for cancer therapy.
Danovi
Davide
D
Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
Meulmeester
Erik
E
Pasini
Diego
D
Migliorini
Domenico
D
Capra
Maria
M
Frenk
Ruth
R
de Graaf
Petra
P
Francoz
Sarah
S
Gasparini
Patrizia
P
Gobbi
Alberto
A
Helin
Kristian
K
Pelicci
Pier Giuseppe
PG
Jochemsen
Aart G
AG
Marine
Jean-Christophe
JC
D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000209:etiology / Q000473:pathology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000473:pathology; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins