The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network

Nuclear exclusion of the PTEN tumour suppressor has been associated with cancer progression1-6. 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 i...

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Main Authors:	Song, Min Sup, Salmena, Leonardo, Carracedo, Arkaitz, Egia, Ainara, Lo-Coco, Francesco, Teruya-Feldstein, Julie, Pandolfi, Pier Paolo
Format:	Online
Language:	English
Published:	2008
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398484/

id	pubmed-3398484
recordtype	oai_dc
spelling	pubmed-33984842012-07-17 The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network Song, Min Sup Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, Francesco Teruya-Feldstein, Julie Pandolfi, Pier Paolo Article Nuclear exclusion of the PTEN tumour suppressor has been associated with cancer progression1-6. 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 partitioning7. 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. 2008-08-20 2008-10-09 /pmc/articles/PMC3398484/ /pubmed/18716620 http://dx.doi.org/10.1038/nature07290 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Song, Min Sup Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, Francesco Teruya-Feldstein, Julie Pandolfi, Pier Paolo
spellingShingle	Song, Min Sup Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, Francesco Teruya-Feldstein, Julie Pandolfi, Pier Paolo The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
author_facet	Song, Min Sup Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, Francesco Teruya-Feldstein, Julie Pandolfi, Pier Paolo
author_sort	Song, Min Sup
title	The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
title_short	The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
title_full	The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
title_fullStr	The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
title_full_unstemmed	The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network
title_sort	deubiquitinylation and localization of pten are regulated by a hausp–pml network
description	Nuclear exclusion of the PTEN tumour suppressor has been associated with cancer progression1-6. 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 partitioning7. 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.
publishDate	2008
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398484/
_version_	1611543503740862464

The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network

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