| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 102 === ABSTRACT
Many studies showed that adenovirus type 5 E1A involves in several anti-cancer abilities such as inhibit tumor progression, increase chemo-drugs sensitization and metastasis suppression. E1A gene therapy have demonstrated antitumor efficacy in several clinical trials but the mechanisms involve in E1A mediated metastasis-inhibition still unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination at K447 by GP78 E3 ubiquitin ligase for subsequent proteasome-mediated degradation. We propose a model in which a crosstalk between two lysine modifications govern the oncogenic function of HSPA5 and also provide insight into how E1A mediates HSPA5 degradation via GP78 to inhibit metastasis. This study indicates HSPA5 as a therapeutic target in breast cancer patients, which can use as a biomarker for E1A gene therapy in future clinical trial. Moreover, our model is the first time to show HSPA5 stability through GP78 E3 ligase mediate ubiquitin-proteosome degradation and the novel cross-talk between two lysine modifications determine the fate and function of HSPA5 in breast cancers.
|
|---|
