Jeong Kwon, Kim Seong-Jin, Oh Yoojung, Kim Hunsung, Lee Young-Seok, Kwon Byung-Su, Park Sanghyun, Park Key-Chung, Yoon Kyung-Sik, Kim Sung Soo, Ha Joohun, Kang Insug, Choe Wonchae
Department of Biochemistry and Molecular Biology (BK21 Project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Biochem Biophys Res Commun. 2014 Nov 28;454(4):518-23. doi: 10.1016/j.bbrc.2014.10.101. Epub 2014 Oct 27.
Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development of many diseases. A previous study indicated that the apoptotic regulator p53 is significantly increased in response to ER stress and participates in ER stress-induced apoptosis. However, the regulators of p53 expression during ER stress are still not fully understood. Here, we investigated whether p53 contributes to the impairment of Pin1 signaling under ER stress. We found that treatment with thapsigargin, a stimulator of p53 expression and an inducer of ER stress, decreased Pin1 expression in HCT116 cells. Also, we identified functional p53 response elements (p53REs) in the Pin1 promoter. Overexpression of p53 significantly decreased Pin1 expression in HCT116 cells while abolition of p53 gene expression induced Pin1 expression. Pin1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-α or down-regulation of p53 expression. Taken together, ER stress decreased Pin1 expression through p53 activation, and this mechanism may be associated with ER stress-induced cell death. These data reported here support the importance of Pin1 as a potential target molecule mediating tumor development.
越来越多的证据表明，内质网（ER）应激在许多疾病的发展中起主要作用。先前的一项研究表明，凋亡调节因子p53在ER应激反应中显著增加，并参与ER应激诱导的细胞凋亡。然而，ER应激期间p53表达的调节因子仍未完全了解。在这里，我们研究了p53是否在ER应激下导致Pin1信号传导受损。我们发现，用毒胡萝卜素处理，一种p53表达的刺激剂和ER应激的诱导剂，可降低HCT116细胞中Pin1的表达。此外，我们在Pin1启动子中鉴定了功能性p53反应元件（p53REs）。p53的过表达显著降低了HCT116细胞中Pin1的表达，而p53基因表达的消除则诱导了Pin1的表达。用p53抑制剂pifithrin-α处理或下调p53表达可显著增加Pin1的表达。综上所述，ER应激通过p53激活降低了Pin1的表达，这种机制可能与ER应激诱导的细胞死亡有关。这里报道的数据支持Pin1作为介导肿瘤发展的潜在靶分子的重要性。
