UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation.
UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation.
复制标题
UBE4B在丝氨酸15和392处靶向磷酸化的p53，以降解。
DOI：
10.18632/oncotarget.6555
复制
发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Leng RP
中科院分区：
文献类型：
--
作者：
Du C;Wu H;Leng RP
p53的磷酸化是其肿瘤抑制功能响应于各种应激而激活的关键机制。在未应激的细胞中，p53迅速翻转并维持在低基础水平。在DNA损伤或其他形式的细胞应激后，p53水平增加，并且蛋白质变得代谢稳定。然而，磷酸化p53的调节机制尚不清楚。在这项研究中，我们研究了响应于p53激活的UBE 4 B、Hdm 2、Pirh 2、Cop 1和CHIP诱导的动力学。我们发现，UBE 4 B与磷酸化p53在丝氨酸15和392共免疫沉淀。值得注意的是，DNA损伤后UBE 4 B和Hdm 2之间的亲和力大大降低。此外，我们观察到，UBE 4 B促进内源性磷酸化p53（S15）和磷酸化p53（S392）的降解反应IR。我们证明，UBE 4 B和Hdm 2抑制p53 S15 A，p53 S392 A，和p53-2A（S15 A，S392 A）的功能，包括p53依赖的反式激活和生长抑制。总之，我们的研究结果表明，UBE 4 B在调节DNA损伤后磷酸化p53中起着重要作用。
Phosphorylation of p53 is a key mechanism responsible for the activation of its tumor suppressor functions in response to various stresses. In unstressed cells, p53 is rapidly turned over and is maintained at a low basal level. After DNA damage or other forms of cellular stress, the p53 level increases, and the protein becomes metabolically stable. However, the mechanism of phosphorylated p53 regulation is unclear. In this study, we studied the kinetics of UBE4B, Hdm2, Pirh2, Cop1 and CHIP induction in response to p53 activation. We show that UBE4B coimmunoprecipitates with phosphorylated p53 at serines 15 and 392. Notably, the affinity between UBE4B and Hdm2 is greatly decreased after DNA damage. Furthermore, we observe that UBE4B promotes endogenous phospho-p53(S15) and phospho-p53(S392) degradation in response to IR. We demonstrate that UBE4B and Hdm2 repress p53S15A, p53S392A, and p53-2A(S15A, S392A) functions, including p53-dependent transactivation and growth inhibition. Overall, our results reveal that UBE4B plays an important role in regulating phosphorylated p53 following DNA damage.