Abstract 1229: E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis

Abstract

Abstract Tumor suppressor p53 plays a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications. Ubiquitination is the most important post-translational modification for p53. TRIM32 is a protein of the tripartite motif (TRIM) family. The proteins of TRIM family have been reported to be involved in different biological processes, including cell growth, differentiation, development, muscular physiology, innate immune response and cancer. However, like the majority of TRIM family proteins, the biological function of TRIM32 is not well-understood. Here, we identified TRIM32 as a novel p53 target gene and E3 ubiquitin ligase for p53. In response to stress, including ionizing radiation (IR) and chemotherapeutic agents (e.g. etoposide and 5-fluorouracil), p53 protein binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 protein interacts with p53 protein and promotes p53 degradation through ubiquitination to negatively regulate p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. Thus, p53 and TRIM32 form a novel negative feedback loop in cells to regulate p53 protein levels and function. TRIM32 is frequently overexpressed in different types of human tumors, including lung, colorectal and liver cancers. TRIM32 overexpression promotes the oncogenic transformation of primary mouse embryonic fibroblasts in a largely p53-dependent manner. Furthermore, TRIM32 overexpression promotes tumorigenesis in mice through the down-regulation of p53 function. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 plays an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis. Citation Format: Cen Zhang, Juan Liu, Xiaolong Wang, Ken H. Young, Wenwei Hu, Zhaohui Feng. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2015-1229