
DOI . ORG {
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Title[redir]:
Identification of a tumour suppressor network opposing nuclear Akt function | Nature
Description:
The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor1. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus. We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice2. We show that Pml deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to pAkt levels, and demonstrate that Pml specifically recruits the Akt phosphatase PP2a as well as pAkt into Pml nuclear bodies. Notably, we find that Pml-null cells are impaired in PP2a phosphatase activity towards Akt, and thus accumulate nuclear pAkt. As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27kip1. Our results demonstrate that Pml orchestrates a nuclear tumour suppressor network for inactivation of nuclear pAkt, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.
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Keywords {π}
article, pubmed, google, scholar, cas, nature, cell, cancer, akt, pml, suppressor, nuclear, pten, access, tumor, content, tumour, pier, paolo, pandolfi, prostate, regulation, cookies, function, data, transcription, pakt, mice, suppression, ads, privacy, information, trotman, ppa, sci, central, essential, alimonti, scaglioni, cordoncardo, human, tumorigenesis, leads, phosphatase, multiple, genet, biol, science, protein, ppp,
Topics {βοΈ}
nature portfolio privacy policy permissions reprints nature cell biol advertising pkb/akt-dependent cell survival social media embryonic development p53-dependent cellular senescence subscribe nature nature genet pml-ii regulates erk high cancer susceptibility nature 436 nature nature 441 author information authors pier paolo pandolfi pier paolo scaglioni p53-dependent apoptosis springerlink instant access author contributions author correspondence permissions information akt signal activation expected tumor suppressor tumour suppressor pml sloan-kettering institute tumor suppressor pten ovarian follicle activation competing financial interests personal data stress-dependent regulation pten tumour suppressor1 privacy suppresses tumor growth metastatic prostate cancer prostate cancer cells pml nuclear bodies permissions proto-oncogene akt pi3kβakt pathway directly dephosphorylates akt pten-deficient tumorigenesis data protection data analysis akt phosphatase pp2a accumulate nuclear pakt cordon-cardo prostate-specific deletion
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headline:Identification of a tumour suppressor network opposing nuclear Akt function
description:The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor1. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus. We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice2. We show that Pml deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to pAkt levels, and demonstrate that Pml specifically recruits the Akt phosphatase PP2a as well as pAkt into Pml nuclear bodies. Notably, we find that Pml-null cells are impaired in PP2a phosphatase activity towards Akt, and thus accumulate nuclear pAkt. As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27kip1. Our results demonstrate that Pml orchestrates a nuclear tumour suppressor network for inactivation of nuclear pAkt, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.
datePublished:2006-05-07T00:00:00Z
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headline:Identification of a tumour suppressor network opposing nuclear Akt function
description:The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor1. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus. We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice2. We show that Pml deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to pAkt levels, and demonstrate that Pml specifically recruits the Akt phosphatase PP2a as well as pAkt into Pml nuclear bodies. Notably, we find that Pml-null cells are impaired in PP2a phosphatase activity towards Akt, and thus accumulate nuclear pAkt. As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27kip1. Our results demonstrate that Pml orchestrates a nuclear tumour suppressor network for inactivation of nuclear pAkt, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.
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Analytics and Tracking {π}
- Google Tag Manager
Libraries {π}
- Prism.js
- Zoom.js
Emails and Hosting {βοΈ}
Mail Servers:
- mx.zoho.eu
- mx2.zoho.eu
- mx3.zoho.eu
Name Servers:
- josh.ns.cloudflare.com
- zita.ns.cloudflare.com
CDN Services {π¦}
- Crossref