Zhu Q, Wani G, Yao J, Patnaik S, Wang Q-E, El-Mahdy M A, Praetorius-Ibba M, Wani A A
Department of Radiology, The Ohio State University, Columbus, OH 43210, USA.
Oncogene. 2007 Jun 21;26(29):4199-208. doi: 10.1038/sj.onc.1210191. Epub 2007 Jan 15.
The ubiquitin (Ub)-proteasome system (UPS) promotes the proteasomal degradation of target proteins by decorating them with Ub labels. Emerging evidence indicates a role of UPS in regulating gene transcription. In this study, we provided evidence for the involvement of UPS in the transcriptional activation function of tumor suppressor p53. We showed that both ubiquitylation and proteasomal functions are required for efficient transcription mediated by p53. Disruption of transcription by actinomycin D, 5,6-dichloro-1-beta-D-ribofuranosyl-benzimadazole or alpha-amanitin leads to accumulation of cellular p53 protein. Proteasome inhibition by MG132 increases the occupancy of p53 protein at p53-responsive p21(waf1) promoter. In addition, the Sug-1 component of 19S proteasome physically interacts with p53 in vitro and in vivo. Moreover, in response to ultraviolet-induced DNA damage, both the 19S proteasomal components, Sug1 and S1, are recruited to p21(waf1) promoter region in a kinetic pattern similar to that of p53. These results suggested that UPS positively regulates p53-mediated transcription at p21(waf1) promoter.
泛素（Ub）-蛋白酶体系统（UPS）通过给靶蛋白标记泛素来促进蛋白酶体对其进行降解。新出现的证据表明UPS在调节基因转录中发挥作用。在本研究中，我们提供了证据证明UPS参与肿瘤抑制因子p53的转录激活功能。我们发现p53介导的有效转录需要泛素化和蛋白酶体功能。放线菌素D、5,6-二氯-1-β-D-呋喃核糖基苯并咪唑或α-鹅膏蕈碱对转录的破坏会导致细胞p53蛋白的积累。MG132对蛋白酶体的抑制作用增加了p53蛋白在p53反应性p21（waf1）启动子上的占有率。此外，19S蛋白酶体的Sug-1组分在体外和体内均与p53发生物理相互作用。而且，响应紫外线诱导的DNA损伤时，19S蛋白酶体组分Sug1和S1均以与p53相似的动力学模式被募集到p21（waf1）启动子区域。这些结果表明，UPS在p21（waf1）启动子上正向调节p53介导的转录。
