Abstract C192: Protein L-isoaspartyl methyltransferase negatively regulates p53 activity.

Abstract

Abstract Protein L-isoaspartyl methyltransferase (PIMT), the “protein repair enzyme,” specifically methylates the isoaspartyl residue generated by the spontaneous deamidation of asparagine, and this methylation is an essential step for converting isoaspartate to aspartate. However, the role of the PIMT in the regulation of protein functions is relatively less understood. Here, we show that PIMT negatively regulates the tumor suppressor protein p53 by reducing the p53 protein levels, thereby suppressing the p53-mediated transcription of target genes. In addition, PIMT depletion up-regulates the proapoptotic and checkpoint activation functions of p53. Moreover, PIMT destabilizes p53 by enhancing the p53-HDM2 interaction. These PIMT effects on p53 stability and activity are attributed to the PIMT-mediated methylation of p53 at isoaspartate residues 29 and 30. Our study provides a new insight into molecular mechanisms by which PIMT suppresses the p53 activity through carboxyl methylation, and suggests a novel therapeutic target for cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C192. Citation Format: Min-Gyu Lee, Jae-Cheol Lee, Ki-Hong Nam, Jihee Yoo, Jeehun Park, Jeung-Whan Han. Protein L-isoaspartyl methyltransferase negatively regulates p53 activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C192.