The role of p53 under ER stress pathway

• Main Authors: Yu-Chi Chuang, 莊毓琪
• Other Authors: Ming-Derg Lai
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/03808158916412893712

碩士 === 國立成功大學 === 生物化學研究所 === 93 === 　Eukaryotic cells have a membranous labyrinth network called the endoplasmic reticulum (ER) that extends through the cytoplasm of the cell and is contiguous with the nuclear envelope. Proteins must be correctly folded and assembled in the ER prior to transit to intracellular organelles and the cell surface. A number of cellular stress conditions lead to accumulation of unfolded or misfolded proteins in the ER lumen. Cells responsed to excess of unfolded proteins in ER are through the well-characterized unfolded protein response (UPR) pathway. If the cells are exposed to prolonged or strong ER stress, the cells are destroyed by apoptosis. The p53 tumor suppressor is a key mediator of the cellular response to stress. Given the role of p53 in stress sensing and proapoptotic signaling, we are interested to investigate whether p53 plays a role in ER stress. Here, our data shows that the expression of p53 reduces in the first six hours after treated with tunicamycin and brefeldin A, two ER stress inducers, the same as a previous study. But interestingly, we find that the expression of p53 will increase six hours after ER stress and that p53 phosphorylation at serine 15 can also be observed 18 hr after ER stress. Ablation of p53 by RNA interference confers cells resistance to ER stress-induced cell death. Semiquantitative RT-PCR shows that the expression of p53 increases following brefeldin A and tunicamycin treatment and the expression can be abolished by treating with cycloheximide. Nuclear translocation of NF-�羠 is observed during ER stress and the induction of p53 can be attenuated by I�羠�屔inase inhibitor Bay 11-7082. Indeed, chromatin immunoprecipitation (ChIP) assay demonstrates that NF-�羠 and p53 itself may bind to p53 promoter to regulate p53 gene expression during ER stress. Furthermore, p53 has little effect on driving downstream genes expression, but phospho-ser15-p53 translocates to mitochondria is detected by western blotting after brefeldin A treatment. Altogether, these data suggest p53 may play a role in ER stress-induced cell death, and the mechanism should be further studied.