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 p14ARFor 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.
Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity / D. Danovi, E. Meulmeester, D. Pasini, D. Migliorini, M. Capra, R. Frenk, P. De Graaf, S. Francoz, P. Gasparini, A. Gobbi, K. Helin, P.G. Pelicci, A.G. Jochemsen, J. Marine. - In: MOLECULAR AND CELLULAR BIOLOGY. - ISSN 0270-7306. - 24:13(2004), pp. 5835-5843.
|Titolo:||Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity|
|Parole Chiave:||Molecular Biology; Cell Biology|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
|Data di pubblicazione:||2004|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1128/MCB.24.13.5835-5843.2004|
|Appare nelle tipologie:||01 - Articolo su periodico|