Abstract 788: Effects of ATF3 on the gain-of-function of mutant p53.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Activating Transcription Factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors and can be rapidly induced by DNA damage and other cellular stresses. We previously found that ATF3 activates p53 by binding to the C-terminus of the tumor suppressor and blocking its ubiquitination, and consequently inhibits cellular transformation. Since TP53 is mutated in half of human cancers and mutant p53 proteins (mutp53) acquire oncogenic activities including promoting drug resistance and driving cancer cell invasion and metastasis, we were interested to explore effects of ATF3 on the mutp53 gain-of-functions (GOF). One major mechanism by which mutp53 promotes tumorigenesis is through binding another p53 family member p63 and inhibiting its tumor suppressor functions. We found that ATF3, but not a mutated ATF3 protein (▵102-139) devoid of its p53-binding region, bind the p53R175H mutant and disrupted the interactions between mutp53 and p63. As a consequence, while mutp53 inhibited the p63 transcriptional activity, ATF3 but not the ▵102-139 protein counteracted mutp53 and resumed p63 activity. Consistent with these results, ATF3 expression inhibited mutp53-promoted cell migration and invasion. In addition to effects on the mutp53-p63 interaction, we also found that ATF3 repressed mutp53-induced NFκB activity, thereby sensitizing mutp53-expressing cells to treatments with etoposide and cisplatin. We conclude that ATF3 suppresses the GOF of mutant p53 and thus may also contribute to tumor suppression in p53-mutated cancer cells. Citation Format: Saisai Wei, Sarah Malmut, Hongbo Wang, Chunhong Yan. Effects of ATF3 on the gain-of-function of mutant p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 788. doi:10.1158/1538-7445.AM2013-788