title: Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Danovi
authors.forename: Erik
authors.initials: E
authors.lastname: Meulmeester
authors.forename: Diego
authors.initials: D
authors.lastname: Pasini
authors.forename: Domenico
authors.initials: D
authors.lastname: Migliorini
authors.forename: Maria
authors.initials: M
authors.lastname: Capra
authors.forename: Ruth
authors.initials: R
authors.lastname: Frenk
authors.forename: Petra
authors.initials: P
authors.lastname: de Graaf
authors.forename: Sarah
authors.initials: S
authors.lastname: Francoz
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Aart G
authors.initials: AG
authors.lastname: Jochemsen
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
mesh_terms: 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
chemical_list: 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