HAUSP在p53-Mdm2通路中的动态作用。
A dynamic role of HAUSP in the p53-Mdm2 pathway.
作者信息
Li Muyang, Brooks Christopher L, Kon Ning, Gu Wei
机构信息
Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
出版信息
Mol Cell. 2004 Mar 26;13(6):879-86. doi: 10.1016/s1097-2765(04)00157-1.
Our previous study showed that ubiquitination of p53 is reversible and that the ubiquitin hydrolase HAUSP can stabilize p53 by deubiquitination. Here, we found that partial reduction of endogenous HAUSP levels by RNAi indeed destabilizes endogenous p53; surprisingly, however, nearly complete ablation of HAUSP stabilizes and activates p53. We further show that this phenomenon occurs because HAUSP stabilizes Mdm2 in a p53-independent manner, providing an interesting feedback loop in p53 regulation. Notably, HAUSP is required for Mdm2 stability in normal cells; in HAUSP-ablated cells, self-ubiquitinated-Mdm2 becomes extremely unstable, leading to indirect p53 activation. Furthermore, this feedback regulation is specific to Mdm2; in HeLa cells, where p53 is preferentially degraded by viral E6-dependent ubiquitination, depletion of HAUSP fails to activate p53. This study provides an example of an ubiquitin ligase (Mdm2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway.
我们之前的研究表明，p53的泛素化是可逆的，泛素水解酶HAUSP可通过去泛素化作用使p53稳定。在此，我们发现，通过RNA干扰使内源性HAUSP水平部分降低确实会使内源性p53不稳定；然而，令人惊讶的是，几乎完全消除HAUSP会使p53稳定并激活。我们进一步表明，出现这种现象是因为HAUSP以不依赖p53的方式使Mdm2稳定，从而在p53调节中形成了一个有趣的反馈环。值得注意的是，在正常细胞中，Mdm2的稳定性需要HAUSP；在消除HAUSP的细胞中，自身泛素化的Mdm2变得极其不稳定，导致间接激活p53。此外，这种反馈调节对Mdm2具有特异性；在p53主要通过病毒E6依赖的泛素化被降解的HeLa细胞中，消除HAUSP无法激活p53。本研究提供了一个由去泛素酶（HAUSP）直接调节泛素连接酶（Mdm2）的例子，同时也揭示了HAUSP在p53-Mdm2途径中的动态作用。
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