Abstract 217: Functional analysis of the protein citrullination through p53/PADI4 network in carcinogenesis

Abstract

Abstract Upon a wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However, its involvement in posttranslational modifications of proteins has not yet been well characterized. We recently reported the novel role of p53 in the regulation of protein citrullination through the transactivation of peptidylarginine deiminase type 4 (PADI4). The PADI4 gene encodes an enzyme catalyzing the citrullination of arginine residues in proteins, and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination. Here we generated the Padi4-deficient mice and examined the role of protein citrullination in vivo. When mice were exposed to X-ray (3 Gy), Padi4 expression was induced in thymus of irradiated wild type mice but not in p53-/- and Padi4-/- mice. Interestingly, TUNEL-positive cells in irradiated thymus were significantly decreased in Padi4-/- mice. Gene expression analysis using irradiated thymus tissues revealed several genes related to the immune response were regulated by Padi4. To further investigate the molecular mechanism whereby PADI4 regulates apoptotic pathway, we surveyed PADI4 substrates and found that various proteins such as core histones were citrullinated in response to DNA damage. These findings demonstrated the significance of PADI4-mediated protein citrullination in the p53 signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 217. doi:10.1158/1538-7445.AM2011-217