文章：

Jun二聚化蛋白2（JDP2）通过降低MDM2增强p53的转录激活功能

Jun Dimerization Protein 2 (JDP2) Increases p53 Transactivation by Decreasing MDM2

原文发布日期：29 February 2024

DOI: 10.3390/cancers16051000

类型: Article

开放获取: 是

英文摘要：

The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target genes. JDP2 has also demonstrates important roles in cell-cycle regulation, cancer development and progression, inhibition of adipocyte differentiation, and the regulation of antibacterial immunity and bone homeostasis. JDP2 and ATF3 exhibit significant similarity in their C-terminal domains, sharing 60–65% identities. Previous studies have demonstrated that ATF3 is able to influence both the transcriptional activity and p53 stability via a p53-ATF3 interaction. While some studies have shown that JDP2 suppresses p53 transcriptional activity and in turn, p53 represses JDP2 promoter activity, the direct interaction between JDP2 and p53 and the regulatory role of JDP2 in p53 transactivation have not been explored. In the current study, we provide evidence, for the first time, that JDP2 interacts with p53 and regulates p53 transactivation. First, we demonstrated that JDP2 binds to p53 and the C-terminal domain of JDP2 is crucial for the interaction. Second, in p53-null H1299 cells, JDP2 shows a robust increase of p53 transactivation in the presence of p53 using p53 (14X)RE-Luc. Furthermore, JDP2 and ATF3 together additively enhance p53 transactivation in the presence of p53. While JDP2 can increase p53 transactivation in the presence of WT p53, JDP2 fails to enhance transactivation of hotspot mutant p53. Moreover, in CHX chase experiments, we showed that JDP2 slightly enhances p53 stability. Finally, our findings indicate that JDP2 has the ability to reverse MDM2-induced p53 repression, likely due to decreased levels of MDM2 by JDP2. In summary, our results provide evidence that JDP2 directly interacts with p53 and decreases MDM2 levels to enhance p53 transactivation, suggesting that JDP2 is a novel regulator of p53 and MDM2.

摘要翻译： 

AP-1蛋白复合物主要由c-Fos、c-Jun、激活转录因子（ATF）和Jun二聚化蛋白（JDP）家族的若干蛋白组成。研究表明JDP2能与下游靶基因多个顺式元件中的cAMP反应元件（CRE）位点相互作用。JDP2在细胞周期调控、癌症发生发展、脂肪细胞分化抑制以及抗菌免疫与骨稳态调节中均发挥重要作用。JDP2与ATF3在C端结构域具有显著相似性，序列一致性达60-65%。既往研究证实ATF3可通过p53-ATF3相互作用影响转录活性和p53稳定性。尽管有研究表明JDP2能抑制p53转录活性，而p53又可抑制JDP2启动子活性，但JDP2与p53的直接相互作用及其对p53反式激活的调控机制尚未阐明。本研究首次证实JDP2能与p53相互作用并调控其反式激活功能。首先，我们证明JDP2可与p53结合，且该相互作用依赖于JDP2的C端结构域。其次，在p53缺失的H1299细胞中，通过p53（14X）RE-Luc报告系统发现JDP2能显著增强p53的反式激活作用。值得注意的是，JDP2与ATF3在p53存在时可协同增强其反式激活功能。虽然JDP2能增强野生型p53的反式激活，但对热点突变型p53无此效应。此外，CHX追踪实验表明JDP2可轻微提升p53稳定性。最后，我们发现JDP2能够逆转MDM2诱导的p53抑制效应，这可能源于JDP2降低了MDM2的表达水平。综上所述，本研究证实JDP2可直接与p53相互作用，并通过降低MDM2水平增强p53反式激活功能，提示JDP2是p53-MDM2通路的新型调控因子。

原文链接：

Jun Dimerization Protein 2 (JDP2) Increases p53 Transactivation by Decreasing MDM2