Abstract
Mutations in the TP53 tumor suppressor gene are the most frequent genetic alteration in human cancers. These alterations are mostly missense point mutations that cluster in the DNA binding domain. There is growing evidence that many of these mutations generate mutant p53 proteins that have acquired new biochemical and biological properties. Through this gain of function activity, mutant p53 is believed to contribute to tumor malignancy. The purpose of our study was to explore mutant p53 as a target for novel anticancer treatments. To this aim, we inhibited mutant p53 expression by RNA interference in three different cancer cell lines endogenously expressing mutant p53 proteins, and evaluated the effects on the biological activities through which mutant p53 exerts gain of function. We found that depletion of mutant p53 reduces cell proliferation, in vitro and in vivo tumorigenicity, and resistance to anticancer drugs. Our results demonstrate that mutant p53 knocking down weakens the aggressiveness of human cancer cells, and provides further insight into the comprehension of mutant p53 gain of function activity in human tumor.
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Acknowledgements
We thank Dr S Soddu for the critical reading of the manuscript. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Salute, Italia-Usa project, Fondo per gli Investimenti della Ricerca di Base (FIRB). This study is part of mutant p53 project, which has received research funding from the community's VI FP. The content of this publication reflects the author's views. European Commission is not liable for any that may be made of this information.
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Bossi, G., Lapi, E., Strano, S. et al. Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 25, 304–309 (2006). https://doi.org/10.1038/sj.onc.1209026
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DOI: https://doi.org/10.1038/sj.onc.1209026
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