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

Davide Danovi, Erik Meulmeester, Diego Pasini, Domenico Migliorini, Maria Capra, Ruth Frenk, Petra De Graaf, Sarah Francoz, Patrizia Gasparini, Alberto Gobbi, Kristian Helin, Pier Giuseppe Pelicci, Aart G. Jochemsen, Jean Christophe Marine

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)5835-5843
Number of pages9
JournalMolecular and Cellular Biology
Volume24
Issue number13
DOIs
Publication statusPublished - Jul 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Fingerprint Dive into the research topics of 'Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity'. Together they form a unique fingerprint.

Cite this