Hes-1 SUMOylation by PIAS1 enhances the suppressing effect of Hes-1 on GADD45alpha expression to increase cell survival

• Main Authors: Hsin-Ying Chiou, 邱馨瑩
• Other Authors: Eminy HY Lee
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/69235821587469578947

博士 === 國防醫學院 === 生命科學研究所 === 102 === Hairy and Enhancer of split 1 (Hes-1) is a transcriptional repressor that plays an important role in neuronal differentiation and development, but post-translational modifications of Hes-1 are much less known. In this study, we have found that Hes-1 could be SUMO-modified and Hes-1 SUMOylation in HEK293T cells was greatly enhanced by the SUMO E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys8, Lys27 and Lys39. Furthermore, Hes-1 SUMOylation stabilized the Hes-1 protein and increased the transcriptional suppressing activity of Hes-1 on growth arrest and DNA damage-inducible protein alpha (GADD45) expression. Overexpression of GADD45 increased, whereas knockdown of GADD45 expression decreased cell apoptosis. In addition, H2O2 treatment increased the association between PIAS1 and Hes-1 and enhanced the SUMOylation of Hes-1 for endogenous protection. Overexpression of Hes-1 decreased H2O2-induced cell death, but this effect was blocked by transfection of the Hes-1 triple sumo-mutant. Overexpression of PIAS1 further facilitated the anti-apoptotic effect of Hes-1. Moreover, Hes-1 SUMOylation was independent of Hes-1 phosphorylation and vice versa. Here, we first demonstrated that GADD45 is a novel target of Hes-1 and Hes-1 could by SUMO-modified by PIAS1. Further, Hes-1 SUMOylation mediates cell survival through enhanced suppression of GADD45 expression.