Data from Therapeutic Efficacy of <i>p53</i> Restoration in <i>Mdm2</i>-Overexpressing Tumors

Abstract

<div>Abstract<p>The <i>p53</i> (TP53) tumor suppressor is the most frequently mutated gene in human cancers. Restoring expression of wild-type <i>p53</i> has led to tumor growth suppression in a variety of tumor models that are <i>p53</i> deficient. Other mechanisms, for example, upregulation of Mdm2, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type <i>p53</i>. In this study, the effects of restoring p53 activity were probed in <i>Mdm2</i>-overexpressing tumors genetically using animal models. Here, it was demonstrated that elevated levels of Mdm2 and decreased levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development. Our data further indicate that restoration of wild-type <i>p53</i> expression in <i>Mdm2</i>-overexpressing angiosarcomas results in tumor stasis and regression in some cases. Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the <i>Mdm2</i>-overexpressing angiosarcomas.</p><p><b>Implications:</b> Restoration of wild-type <i>p53</i> expression in <i>Mdm2</i>-overexpressing tumors suppresses tumor growth, which represents a potential clinical strategy to treat tumors with high levels of Mdm2.</p><p><b>Visual Overview:</b> <a href="http://mcr.aacrjournals.org/content/12/6/901/F1.large.jpg" target="_blank">http://mcr.aacrjournals.org/content/12/6/901/F1.large.jpg</a>.</p><p><i>Mol Cancer Res; 12(6); 901–11. ©2014 AACR</i>.</p></div>