Amplification of Mdmx (or Mdm4 ) Directly Contributes to Tumor Formation by Inhibiting p53 Tumor Suppressor Activity

  • Danovi D
  • Meulmeester E
  • Pasini D
  • et al.
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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.

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APA

Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., … Marine, J.-C. (2004). Amplification of Mdmx (or Mdm4 ) Directly Contributes to Tumor Formation by Inhibiting p53 Tumor Suppressor Activity. Molecular and Cellular Biology, 24(13), 5835–5843. https://doi.org/10.1128/mcb.24.13.5835-5843.2004

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