The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling.
The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling.
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去泛素化酶（DUBs）可以逆转泛素连接酶催化的修饰，因此被认为是多种细胞过程的重要调节因子。该蛋白家族的几个成员与人类癌症有关；然而，几乎没有证据表明不受管制的去泛素化与肿瘤转化之间存在直接联系。泛素c端水解酶（Ubiquitin C-terminal hydrolase， UCH）-L1是一种功能未知的DUB，在几种人类癌症中过度表达，但其是否具有致癌特性尚未确定。为了解决这个问题，我们产生了在无所不在的启动子控制下过表达UCH-L1的小鼠。在这里，我们发现UCH-L1转基因小鼠容易发生恶性肿瘤，主要是淋巴瘤和肺肿瘤。此外，UCH-L1过表达强烈地加速了Eμ-myc转基因小鼠的淋巴瘤发生。异常表达的UCH-L1通过下调拮抗磷酸酶PHLPP1来促进Akt通路的信号传导，这一事件需要其去泛素酶活性。这些数据首次提供了dub驱动肿瘤发生的体内证据，并表明UCH-L1过度活跃会解除正常Akt信号的调节。
De-ubiquitinating enzymes (DUBs) can reverse the modifications catalyzed by ubiquitin ligases and as such are believed to be important regulators of a variety of cellular processes. Several members of this protein family have been associated with human cancers; however, there is little evidence for a direct link between deregulated de-ubiquitination and neoplastic transformation. Ubiquitin C-terminal hydrolase (UCH)-L1 is a DUB of unknown function that is overexpressed in several human cancers, but whether it has oncogenic properties has not been established. To address this issue, we generated mice that overexpress UCH-L1 under the control of a ubiquitous promoter. Here, we show that UCH-L1 transgenic mice are prone to malignancy, primarily lymphomas and lung tumors. Furthermore, UCH-L1 overexpression strongly accelerated lymphomagenesis in Eμ-myc transgenic mice. Aberrantly expressed UCH-L1 boosts signaling through the Akt pathway by downregulating the antagonistic phosphatase PHLPP1, an event that requires its de-ubiquitinase activity. These data provide the first in vivo evidence for DUB-driven oncogenesis and suggest that UCH-L1 hyperactivity deregulates normal Akt signaling.
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