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Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity

par Danovi, Davide;Meulmeester, Erik;Pasini, Diego;Migliorini, Domenico;Capra, Maria;Frenk, Ruth;De Graaf, Petra;Francoz, Sarah;Gasparini, Patrizia;Gobbi, Alberto;Helin, Kristian;Pelicci, Pier Giuseppe;Jochemsen, Aart;Marine, Jean-Christophe
Référence Molecular and cellular biology, 24, 13, page (5835-5843)
Publication Publié, 2004-07

Article révisé par les pairs

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Résumé :

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 p14ARF 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 HRasV12. 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.