Abstract 2480: Ubiquitination of p53 by Trim39

Trim39 is a RING domain-containing E3 ubiquitin ligase able to directly inhibit the anaphase promoting complex (APC/C). Through analysis of Trim39 function in p53-positive and p53-negative cells we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from dis-inhibition of the APC/C. Moreover, while Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knock-down in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, MDM2, varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with wild type p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis. Citation Format: Liguo Zhang, Chen Chen, Naijia Huang, Wanli Tang, Sally Kornbluth. Ubiquitination of p53 by Trim39. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2014-2480