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Molecular and Cellular Biology, July 2004, p. 5835-5843, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5835-5843.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Davide Danovi,1,{dagger} Erik Meulmeester,2,{dagger} Diego Pasini,1 Domenico Migliorini,1 Maria Capra,1,3 Ruth Frenk,2 Petra de Graaf,2 Sarah Francoz,4,5 Patrizia Gasparini,1,3 Alberto Gobbi,1,3 Kristian Helin,1,3 Pier Giuseppe Pelicci,1,3,{dagger} Aart G. Jochemsen,2,{dagger} and Jean-Christophe Marine1,5,{dagger}*

Department of Experimental Oncology, European Institute of Oncology, 20141 Milan,1 FIRC Institute of Molecular Oncology, 20139 Milan, Italy,3 Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RA Leiden, The Netherlands,2 Unit of Molecular Embryology, Free University of Brussels, B-6041 Gosselies,4 Laboratory of Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, B-9052 Ghent, Belgium5

Received 2 October 2003/ Returned for modification 5 December 2003/ Accepted 12 March 2004

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.

* Corresponding author. Mailing address: Laboratory of Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, B-9052 Ghent, Belgium. Phone: 32 (0)9 33 13 640. Fax: 32 (0)9 33 13 609. E-mail: chris.marine{at}dmbr.ugent.be.

{dagger} D.D., E.M., P.G.P., A.G.J., and J.-C.M. contributed equally to this work.

Molecular and Cellular Biology, July 2004, p. 5835-5843, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5835-5843.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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