The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network.
The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network.
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DOI：
10.1038/nature07290
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发表时间：
2008-10-09
期刊：
影响因子：
64.8
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Song, Min Sup;Salmena, Leonardo;Carracedo, Arkaitz;Egia, Ainara;Lo-Coco, Francesco;Teruya-Feldstein, Julie;Pandolfi, Pier Paolo
PTEN肿瘤抑制因子的核排斥与癌症进展相关。然而，导致人类癌症中这种异常PTEN定位的机制目前尚不清楚。我们以前曾报道过，在特定的赖氨酸残基的PTEN泛素化调节其核质分区。在这里，我们表明，功能PML核体协调PTEN本地化的反对行动的一种新的PTEN-去泛素化酶，HAUSP，这一分子框架的完整性是必需的PTEN能够进入细胞核。我们发现，PTEN异常定位于急性早幼粒细胞白血病（APL），其中PML功能被PML-RARα融合癌蛋白破坏。值得注意的是，用触发PML-RARα降解的药物治疗，如全反式维甲酸或三氧化二砷，恢复了核PTEN。我们证明，PML反对HAUSP对PTEN的活性，通过一种机制，涉及衔接蛋白DAXX。为了支持这一范例，我们发现HAUSP在人前列腺癌中过表达，并与PTEN核排斥相关。因此，我们的研究结果描绘了一种新的PML-DAXX-HAUSP分子网络控制PTEN去泛素化和运输，这是由人类癌症中的致癌线索干扰，反过来定义了一个新的去泛素化依赖模型的PTEN亚细胞区室化。
Nuclear exclusion of the PTEN tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional PML-nuclear bodies co-ordinate PTEN localization by opposing the action of a novel PTEN-deubiquitinylating enzyme, HAUSP, and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia (APL), where PML function is disrupted by the PML-RARα fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARα degradation such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN, through a mechanism involving the adaptor protein DAXX. In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus our results delineate a novel PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.
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