The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network
Open accessAbstract
Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) 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 promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), 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, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha 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 (death domain-associated protein). 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 previously unknown 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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HAUSP is predominantly localized in the nucleus.
“The majority of HAUSP is localized in the nucleus”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Song et al., 2008
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- Authors
- Song, M. S., Salmena, L., Carracedo, A., Egia, A., Lo-Coco, F., Teruya-Feldstein, J., & Pandolfi, P. P.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Pandolfi, Pier Paolo
- Venue
- Nature
- Published
- 2008-08-20
- Volume
- 455
- Issue
- 7214
- Pages
- 813-817
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3398484
- OpenAlex
- W2162648910
- Cited by
- 548
- References
- 34
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 22 · 2023: 35 · 2022: 25 · 2021: 37 · 2020: 43 · 2019: 40 · 2018: 33 · 2017: 39 · 2016: 34 · 2015: 36 · 2014: 32 · 2013: 27 · 2012: 31
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- European Molecular Biology Organization
- National Institutes of Health
- National Cancer Institute (R01CA082328, P50CA092629)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PTEN, USP7, PML, nuclear localization, PML nuclear bodies, DAXX, PML-RARA fusion, acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, prostate cancer, tumor suppressor regulation, ubiquitination, nuclear-cytoplasmic trafficking
- MeSH terms
- Promyelocytic Leukemia Protein, Ubiquitin-Specific Peptidase 7, Animals, Cell Nucleus, Fibroblasts, Humans, Male, Nuclear Proteins, Prostatic Neoplasms, Transcription Factors, Tretinoin, Ubiquitins, Leukemia, Promyelocytic, Acute, Apoptosis, Molecular Chaperones, Active Transport, Cell Nucleus, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, PTEN Phosphohydrolase, Mice, Ubiquitination, Co-Repressor Proteins
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